@article{LamatschTrifonovSchoriesetal.2011, author = {Lamatsch, D. K. and Trifonov, V. and Schories, S. and Epplen, J. T. and Schmid, M. and Schartl, M.}, title = {Isolation of a Cancer-Associated Microchromosome in the Sperm-Dependent Parthenogen Poecilia formosa}, series = {Cytogenetic and Genome Research}, volume = {135}, journal = {Cytogenetic and Genome Research}, number = {2}, issn = {1424-8581}, doi = {10.1159/000331271}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196785}, pages = {135-142}, year = {2011}, abstract = {In the asexual all-female fish species Poecilia formosa, the Amazon molly, supernumerary chromosomes have frequently been found in both laboratory-reared and wild-caught individuals. While wild-caught individuals with B chromosomes are phenotypically indifferent from conspecifics, individuals carrying B chromosomes from recent introgression events in the laboratory show phenotypic changes. Former analyses showed that the expression of a pigment cell locus is associated with the presence of these B chromosomes. In addition, they contain a so far unidentified locus that confers a higher susceptibility to tumor formation in the presence of pigmentation pattern. Isolation by microdissection and hybridization to metaphase chromosomes revealed that they contain one or several sequences with similarity to a highly repetitive pericentromeric and subtelomeric sequence in A chromosomes. Isolation of one particular sequence by AFLP showed that the B chromosomes contain at least 1 copy of an A-chromosomal region which is highly conserved in the whole genus Poecilia, i.e. more than 5 million years old. We propose it to be a single copy sequence.}, language = {en} } @article{SchneiderElHajjHaaf2014, author = {Schneider, Eberhard and El Hajj, Nady and Haaf, Thomas}, title = {Epigenetic Information from Ancient DNA Provides New Insights into Human Evolution}, series = {Brain, Behavior and Evolution}, volume = {84}, journal = {Brain, Behavior and Evolution}, number = {3}, issn = {0006-8977}, doi = {10.1159/000365650}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196800}, pages = {169-171}, year = {2014}, abstract = {No abstract available.}, language = {en} } @article{CamachoSchmidCabrero2011, author = {Camacho, J.P.M. and Schmid, M. and Cabrero, J.}, title = {B Chromosomes and Sex in Animals}, series = {Sexual Development}, volume = {5}, journal = {Sexual Development}, number = {3}, issn = {1661-5425}, doi = {10.1159/000324930}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196321}, pages = {155-166}, year = {2011}, abstract = {Supernumerary (B) chromosomes are dispensable elements found in many eukaryote genomes in addition to standard (A) chromosomes. In many respects, B chromosomes resemble sex chromosomes, so that a common ancestry for them has frequently been suggested. For instance, B chromosomes in grasshoppers, and other insects, show a pycnotic cycle of condensation-decondensation during meiosis remarkably similar to that of the X chromosome. In some cases, B chromosome size is even very similar to that of the X chromosome. These resemblances have led to suggest the X as the B ancestor in many cases. In addition, sex chromosome origin from B chromosomes has also been suggested. In this article, we review the existing evidence for both evolutionary pathways, as well as sex differences for B frequency at adult and embryo progeny levels, B chromosome effects or B chromosome transmission. In addition, we review cases found in the literature showing sex-ratio distortion associated with B chromosome presence, the most extreme case being the paternal sex ratio (PSR) chromosomes in some Hymenoptera. We finally analyse the possibility of B chromosome regularisation within the host genome and, as a consequence of it, whether B chromosomes can become regular members of the host genome.}, language = {en} } @article{PootHaaf2015, author = {Poot, Martin and Haaf, Thomas}, title = {Mechanisms of Origin, Phenotypic Effects and Diagnostic Implications of Complex Chromosome Rearrangements}, series = {Molecular Syndromology}, volume = {6}, journal = {Molecular Syndromology}, number = {3}, issn = {1661-8769}, doi = {10.1159/000438812}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196524}, pages = {110-134}, year = {2015}, abstract = {Complex chromosome rearrangements (CCRs) are currently defined as structural genome variations that involve more than 2 chromosome breaks and result in exchanges of chromosomal segments. They are thought to be extremely rare, but their detection rate is rising because of improvements in molecular cytogenetic technology. Their population frequency is also underestimated, since many CCRs may not elicit a phenotypic effect. CCRs may be the result of fork stalling and template switching, microhomology-mediated break-induced repair, breakage-fusion-bridge cycles, or chromothripsis. Patients with chromosomal instability syndromes show elevated rates of CCRs due to impaired DNA double-strand break responses during meiosis. Therefore, the putative functions of the proteins encoded by ATM, BLM, WRN, ATR, MRE11, NBS1, and RAD51 in preventing CCRs are discussed. CCRs may exert a pathogenic effect by either (1) gene dosage-dependent mechanisms, e.g. haploinsufficiency, (2) mechanisms based on disruption of the genomic architecture, such that genes, parts of genes or regulatory elements are truncated, fused or relocated and thus their interactions disturbed - these mechanisms will predominantly affect gene expression - or (3) mixed mutation mechanisms in which a CCR on one chromosome is combined with a different type of mutation on the other chromosome. Such inferred mechanisms of pathogenicity need corroboration by mRNA sequencing. Also, future studies with in vitro models, such as inducible pluripotent stem cells from patients with CCRs, and transgenic model organisms should substantiate current inferences regarding putative pathogenic effects of CCRs. The ramifications of the growing body of information on CCRs for clinical and experimental genetics and future treatment modalities are briefly illustrated with 2 cases, one of which suggests KDM4C(JMJD2C) as a novel candidate gene for mental retardation.}, language = {en} } @article{HeinrichNandaRehnetal.2013, author = {Heinrich, T. and Nanda, I. and Rehn, M. and Zollner, U. and Frieauff, E. and Wirbelauer, J. and Grimm, T. and Schmid, M.}, title = {Live-Born Trisomy 22: Patient Report and Review}, series = {Molecular Syndromology}, volume = {3}, journal = {Molecular Syndromology}, number = {6}, issn = {1661-8769}, doi = {10.1159/000346189}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196535}, pages = {262-269}, year = {2013}, abstract = {Trisomy 22 is a common trisomy in spontaneous abortions. In contrast, live-born trisomy 22 is rarely seen due to severe organ malformations associated with this condition. Here, we report on a male infant with complete, non-mosaic trisomy 22 born at 35 + 5 weeks via caesarean section. Peripheral blood lymphocytes and fibroblasts showed an additional chromosome 22 in all metaphases analyzed (47,XY,+22). In addition, array CGH confirmed complete trisomy 22. The patient's clinical features included dolichocephalus, hypertelorism, flattened nasal bridge, dysplastic ears with preauricular sinuses and tags, medial cleft palate, anal atresia, and coronary hypospadias with scrotum bipartitum. Essential treatment was implemented in close coordination with the parents. The child died 29 days after birth due to respiratory insufficiency and deterioration of renal function. Our patient's history complements other reports illustrating that children with complete trisomy 22 may survive until birth and beyond.}, language = {en} } @article{AlmanzarKleinSchmalzingetal.2016, author = {Almanzar, Giovanni and Klein, Matthias and Schmalzing, Marc and Hilligardt, Deborah and El Hajj, Nady and Kneitz, Hermann and Wild, Vanessa and Rosenwald, Andreas and Benoit, Sandrine and Hamm, Henning and Tony, Hans-Peter and Haaf, Thomas and Goebeler, Matthias and Prelog, Martina}, title = {Disease Manifestation and Inflammatory Activity as Modulators of Th17/Treg Balance and RORC/FoxP3 Methylation in Systemic Sclerosis}, series = {International Archives of Allergy and Immunology}, volume = {171}, journal = {International Archives of Allergy and Immunology}, number = {2}, issn = {1018-2438}, doi = {10.1159/000450949}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196577}, pages = {141-154}, year = {2016}, abstract = {Background: There is much evidence that T cells are strongly involved in the pathogenesis of localized and systemic forms of scleroderma (SSc). A dysbalance between FoxP3+ regulatory CD4+ T cells (Tregs) and inflammatory T-helper (Th) 17 cells has been suggested. Methods: The study aimed (1) to investigate the phenotypical and functional characteristics of Th17 and Tregs in SSc patients depending on disease manifestation (limited vs. diffuse cutaneous SSc, dcSSc) and activity, and (2) the transcriptional level and methylation status of Th17- and Treg-specific transcription factors. Results: There was a concurrent accumulation of circulating peripheral IL-17-producing CCR6+ Th cells and FoxP3+ Tregs in patients with dcSSc. At the transcriptional level, Th17- and Treg-associated transcription factors were elevated in SSc. A strong association with high circulating Th17 and Tregs was seen with early, active, and severe disease presentation. However, a diminished suppressive function on autologous lymphocytes was found in SSc-derived Tregs. Significant relative hypermethylation was seen at the gene level for RORC1 and RORC2 in SSc, particularly in patients with high inflammatory activity. Conclusions: Besides the high transcriptional activity of T cells, attributed to Treg or Th17 phenotype, in active SSc disease, Tregs may be insufficient to produce high amounts of IL-10 or to control proliferative activity of effector T cells in SSc. Our results suggest a high plasticity of Tregs strongly associated with the Th17 phenotype. Future directions may focus on enhancing Treg functions and stabilization of the Treg phenotype.}, language = {en} } @article{SchmidSteinlein2016, author = {Schmid, Michael and Steinlein, Claus}, title = {Chromosome Banding in Amphibia. XXXIV. Intrachromosomal Telomeric DNA Sequences in Anura}, series = {Cytogenetic and Genome Research}, volume = {148}, journal = {Cytogenetic and Genome Research}, number = {2-3}, issn = {1424-8581}, doi = {10.1159/000446298}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196693}, pages = {211-226}, year = {2016}, abstract = {The mitotic chromosomes of 4 anuran species were examined by various classical banding techniques and by fluorescence in situ hybridization using a (TTAGGG)\(_n\) repeat. Large intrachromosomal telomeric sequences (ITSs) were demonstrated in differing numbers and chromosome locations. A detailed comparison of the present results with numerous published and unpublished data allowed a consistent classification of the various categories of large ITSs present in the genomes of anurans and other vertebrates. The classification takes into consideration the total numbers of large ITSs in the karyotypes, their chromosomal locations and their specific distribution patterns. A new category of large ITSs was recognized to exist in anuran species. It consists of large clusters of ITSs located in euchromatic chromosome segments, which is in clear contrast to the large ITSs in heterochromatic chromosome regions known in vertebrates. The origin of the different categories of large ITSs in heterochromatic and euchromatic chromosome regions, their mode of distribution in the karyotypes and evolutionary fixation in the genomes, as well as their cytological detection are discussed.}, language = {en} } @article{SchmidSteinleinLombetal.2016, author = {Schmid, Michael and Steinlein, Claus and Lomb, Christian and Sperling, Karl and Neitzel, Heidemarie}, title = {5-Methylcytosine-Rich Heterochromatin in the Indian Muntjac}, series = {Cytogenetic and Genome Research}, volume = {147}, journal = {Cytogenetic and Genome Research}, number = {4}, issn = {1424-8581}, doi = {10.1159/000444431}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196701}, pages = {240-246}, year = {2016}, abstract = {Two 5-methylcytosine (5-MeC)-rich heterochromatic regions were demonstrated in metaphase chromosomes of the Indian muntjac by indirect immunofluorescence using a monoclonal anti-5-MeC antibody. The metaphases were obtained from diploid and triploid cell lines. A major region is located in the 'neck' of the 3;X fusion chromosome and can be detected after denaturation of the chromosomal DNA with UV-light irradiation for 1 h. It is located exactly at the border of the X chromosome and the translocated autosome 3. A minor region is found in the centromeric region of the free autosome 3 after denaturing the chromosomal DNA for 3 h or longer. The structure and possible function of the major hypermethylated region as barrier against spreading of the X-inactivation process into the autosome 3 is discussed.}, language = {en} } @article{SchmidSteinleinYanoetal.2016, author = {Schmid, Michael and Steinlein, Claus and Yano, Cassia F. and Cioffi, Marcelo B.}, title = {Hypermethylated Chromosome Regions in Nine Fish Species with Heteromorphic Sex Chromosomes}, series = {Cytogenetic and Genome Research}, volume = {147}, journal = {Cytogenetic and Genome Research}, number = {2-3}, issn = {1424-8581}, doi = {10.1159/000444067}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196710}, pages = {169-178}, year = {2016}, abstract = {Sites and amounts of 5-methylcytosine (5-MeC)-rich chromosome regions were detected in the karyotypes of 9 Brazilian species of Characiformes fishes by indirect immunofluorescence using a monoclonal anti-5-MeC antibody. These species, belonging to the genera Leporinus, Triportheus and Hoplias, are characterized by highly differentiated and heteromorphic ZW and XY sex chromosomes. In all species, the hypermethylated regions are confined to constitutive heterochromatin. The number and chromosome locations of hypermethylated heterochromatic regions in the karyotypes are constant and species-specific. Generally, heterochromatic regions that are darkly stained by the C-banding technique are distinctly hypermethylated, but several of the brightly fluorescing hypermethylated regions merely exhibit moderate or faint C-banding. The ZW and XY sex chromosomes of all 9 analyzed species also show species-specific heterochromatin hypermethylation patterns. The analysis of 5-MeC-rich chromosome regions contributes valuable data for comparative cytogenetics of closely related species and highlights the dynamic process of differentiation operating in the repetitive DNA fraction of sex chromosomes.}, language = {en} } @article{SchmidSteinlein2015, author = {Schmid, Michael and Steinlein, Claus}, title = {Chromosome Banding in Amphibia. XXXII. The Genus Xenopus (Anura, Pipidae)}, series = {Cytogenetic and Genome Research}, volume = {145}, journal = {Cytogenetic and Genome Research}, number = {3-4}, issn = {1424-8581}, doi = {10.1159/000433481}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196727}, pages = {201-217}, year = {2015}, abstract = {Mitotic chromosomes of 16 species of the frog genus Xenopus were prepared from kidney and lung cell cultures. In the chromosomes of 7 species, high-resolution replication banding patterns could be induced by treating the cultures with 5-bromodeoxyuridine (BrdU) and deoxythymidine (dT) in succession, and in 6 of these species the BrdU/dT-banded chromosomes could be arranged into karyotypes. In the 3 species of the clade with 2n = 20 and 4n = 40 chromosomes (X. tropicalis, X. epitropicalis, X. new tetraploid 1), as well as in the 3 species with 4n = 36 chromosomes (X. laevis, X. borealis, X. muelleri), the BrdU/dT-banded karyotypes show a high degree of homoeology, though differences were detected between these groups. Translocations, inversions, insertions or sex-specific replication bands were not observed. Minor replication asynchronies found between chromosomes probably involve heterochromatic regions. BrdU/dT replication banding of Xenopus chromosomes provides the landmarks necessary for the exact physical mapping of genes and repetitive sequences. FISH with an X. laevis 5S rDNA probe detected multiple hybridization sites at or near the long-arm telomeric regions in most chromosomes of X. laevis and X. borealis, whereas in X. muelleri, the 5S rDNA sequences are located exclusively at the long-arm telomeres of a single chromosome pair. Staining with the AT base pair-specific fluorochrome quinacrine mustard revealed brightly fluorescing heterochromatic regions in the majority of X. borealis chromosomes which are absent in other Xenopus species.}, language = {en} } @article{SchmidEvansBogart2015, author = {Schmid, Michael and Evans, Ben J. and Bogart, James P.}, title = {Polyploidy in Amphibia}, series = {Cytogenetic and Genome Research}, volume = {145}, journal = {Cytogenetic and Genome Research}, number = {3-4}, issn = {1424-8581}, doi = {10.1159/000431388}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196730}, pages = {315-330}, year = {2015}, abstract = {This review summarizes the current status of the known extant genuine polyploid anuran and urodelan species, as well as spontaneously originated and/or experimentally produced amphibian polyploids. The mechanisms by which polyploids can originate, the meiotic pairing configurations, the diploidization processes operating in polyploid genomes, the phenomenon of hybridogenesis, and the relationship between polyploidization and sex chromosome evolution are discussed. The polyploid systems in some important amphibian taxa are described in more detail.}, language = {en} } @article{MatsudaUnoKondoetal.2015, author = {Matsuda, Yoichi and Uno, Yoshinobu and Kondo, Mariko and Gilchrist, Michael J. and Zorn, Aaron M. and Rokhsar, Daniel S. and Schmid, Michael and Taira, Masanori}, title = {A New Nomenclature of Xenopus laevis Chromosomes Based on the Phylogenetic Relationship to Silurana/Xenopus tropicalis}, series = {Cytogenetic and Genome Research}, volume = {145}, journal = {Cytogenetic and Genome Research}, number = {3-4}, issn = {1424-8581}, doi = {10.1159/000381292}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196748}, pages = {187-191}, year = {2015}, abstract = {Xenopus laevis (XLA) is an allotetraploid species which appears to have undergone whole-genome duplication after the interspecific hybridization of 2 diploid species closely related to Silurana/Xenopus tropicalis (XTR). Previous cDNA fluorescence in situ hybridization (FISH) experiments have identified 9 sets of homoeologous chromosomes in X. laevis, in which 8 sets correspond to chromosomes 1-8 of X. tropicalis (XTR1-XTR8), and the last set corresponds to a fusion of XTR9 and XTR10. In addition, recent X. laevis genome sequencing and BAC-FISH experiments support this physiological relationship and show no gross chromosome translocation in the X. laevis karyotype. Therefore, for the benefit of both comparative cytogenetics and genome research, we here propose a new chromosome nomenclature for X. laevis based on the phylogenetic relationship and chromosome length, i.e. XLA1L, XLA1S, XLA2L, XLA2S, and so on, in which the numbering of XLA chromosomes corresponds to that in X. tropicalis and the postfixes 'L' and 'S' stand for 'long' and 'short' chromosomes in the homoeologous pairs, which can be distinguished cytologically by their relative size. The last chromosome set is named XLA9L and XLA9S, in which XLA9 corresponds to both XTR9 and XTR10, and hence, to emphasize the phylogenetic relationship to X. tropicalis, XLA9_10L and XLA9_10S are also used as synonyms.}, language = {en} } @article{SchmidSteinleinFeichtingeretal.2014, author = {Schmid, Michael and Steinlein, Claus and Feichtinger, Wolfgang and Haaf, Thomas and Mijares-Urrutia, Abraham and Schargel, Walter E. and Hedges, S. Blair}, title = {Cytogenetic Studies on Gonatodes (Reptilia, Squamata, Sphaerodactylidae)}, series = {Cytogenetic and Genome Research}, volume = {144}, journal = {Cytogenetic and Genome Research}, number = {1}, issn = {1424-8581}, doi = {10.1159/000367929}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196753}, pages = {47-61}, year = {2014}, abstract = {Mitotic and meiotic chromosomes of 5 species of the reptile genus Gonatodes are described by means of conventional staining, banding analyses and in situ hybridization using a synthetic telomeric DNA probe. The amount, location and fluorochrome affinities of constitutive heterochromatin, the number and positions of nucleolus organizer regions, and the patterns of telomeric DNA sequences were determined for most of the species. The karyotypes of G. falconensis and G. taniae from northern Venezuela are distinguished by their extraordinarily reduced diploid chromosome number of 2n = 16, which is the lowest value found so far in reptiles. In contrast to most other reptiles, both species have exclusively large biarmed (meta- and submetacentric) chromosomes. Comparison of the karyotypes of G. falconensis and G. taniae with those of other Gonatodes species indicates that the exceptional 2n = 16 karyotype originated by a series of 8 centric fusions. The karyotypes of G. falconensis and G. taniae are further characterized by the presence of considerable amounts of (TTAGGG)n telomeric sequences in the centromeric regions of all chromosomes. These are probably not only relics of the centric fusion events, but a component of the highly repetitive DNA in the constitutive heterochromatin of the chromosomes. The genome sizes of 4 Gonatodes species were determined using flow cytometry. For comparative purposes, all previously published cytogenetic data on Gonatodes and other sphaerodactylids are included and discussed.}, language = {en} } @article{SchmidSteinleinFeichtingeretal.2014, author = {Schmid, Michael and Steinlein, Claus and Feichtinger, Wolfgang and Bogart, James P.}, title = {Chromosome Banding in Amphibia. XXXI. The Neotropical Anuran Families Centrolenidae and Allophrynidae}, series = {Cytogenetic and Genome Research}, volume = {142}, journal = {Cytogenetic and Genome Research}, number = {4}, issn = {1424-8581}, doi = {10.1159/000362216}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196763}, pages = {268-285}, year = {2014}, abstract = {The mitotic chromosomes of 11 species from the anuran families Centrolenidae and Allophrynidae were analyzed by means of conventional staining, banding techniques, and in situ hybridization. The amount, location, and fluorochrome affinities of constitutive heterochromatin, the number and positions of nucleolus organizer regions, and the patterns of telomeric DNA sequences were determined for most of the species. The karyotypes were found to be highly conserved with a low diploid chromosome number of 2n = 20 and morphologically similar chromosomes. The sister group relationship between the Centrolenidae and Allophrynidae (unranked taxon Allocentroleniae) is clearly corroborated by the cytogenetic data. The existence of heteromorphic XY♂/XX♀ sex chromosomes in an initial stage of morphological differentiation was confirmed in Vitreorana antisthenesi. The genome sizes of 4 centrolenid species were determined using flow cytometry. For completeness and for comparative purposes, all previously published cytogenetic data on centrolenids are included.}, language = {en} } @article{FockenSteinemannSkawranetal.2011, author = {Focken, T. and Steinemann, D. and Skawran, B. and Hofmann, W. and Ahrens, P. and Arnold, N. and Kroll, P. and Kreipe, H. and Schlegelberger, B. and Gadzicki, D.}, title = {Human BRCA1-associated breast cancer: No increase in numerical chromosomal instability compared to sporadic tumors}, series = {Cytogenetic and Genome Research}, volume = {135}, journal = {Cytogenetic and Genome Research}, number = {2}, issn = {1424-8581}, doi = {10.1159/000332005}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196770}, pages = {84 -- 92}, year = {2011}, abstract = {BRCA1 is a major gatekeeper of genomic stability. Acting in multiple central processes like double-strand break repair, centrosome replication, and checkpoint control, BRCA1 participates in maintaining genomic integrity and protects the cell against genomic instability. Chromosomal instability (CIN) as part of genomic instability is an inherent characteristic of most solid tumors and is also involved in breast cancer development. In this study, we determined the extent of CIN in 32 breast cancer tumors of women with a BRCA1 germline mutation compared to 62 unselected breast cancers. We applied fluorescence in situ hybridization (FISH) with centromere-specific probes for the chromosomes 1, 7, 8, 10, 17, and X and locus-specific probes for 3q27 (BCL6), 5p15.2 (D5S23), 5q31 (EGR1), 10q23.3 (PTEN), and 14q32 (IGH@) on formalin-fixed paraffin-embedded tissue microarray sections. Our hypothesis of an increased level of CIN in BRCA1-associated breast cancer could not be confirmed by this approach. Surprisingly, we detected no significant difference in the extent of CIN in BRCA1-mutated versus sporadic tumors. The only exception was the CIN value for chromosome 1. Here, the extent of CIN was slightly higher in the group of sporadic tumors.}, language = {en} } @article{MaierhoferFlunkertOshimaetal.2019, author = {Maierhofer, Anna and Flunkert, Julia and Oshima, Junko and Martin, George M. and Poot, Martin and Nanda, Indrajit and Dittrich, Marcus and M{\"u}ller, Tobias and Haaf, Thomas}, title = {Epigenetic signatures of Werner syndrome occur early in life and are distinct from normal epigenetic aging processes}, series = {Aging Cell}, volume = {18}, journal = {Aging Cell}, doi = {10.1111/acel.12995}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-202733}, pages = {e12995}, year = {2019}, abstract = {Werner Syndrome (WS) is an adult-onset segmental progeroid syndrome. Bisulfite pyrosequencing of repetitive DNA families revealed comparable blood DNA methylation levels between classical (18 WRN-mutant) or atypical WS (3 LMNA-mutant and 3 POLD1-mutant) patients and age- and sex-matched controls. WS was not associated with either age-related accelerated global losses of ALU, LINE1, and α-satellite DNA methylations or gains of rDNA methylation. Single CpG methylation was analyzed with Infinium MethylationEPIC arrays. In a correspondence analysis, atypical WS samples clustered together with the controls and were clearly separated from classical WS, consistent with distinct epigenetic pathologies. In classical WS, we identified 659 differentially methylated regions (DMRs) comprising 3,656 CpG sites and 613 RefSeq genes. The top DMR was located in the HOXA4 promoter. Additional DMR genes included LMNA, POLD1, and 132 genes which have been reported to be differentially expressed in WRN-mutant/depleted cells. DMRs were enriched in genes with molecular functions linked to transcription factor activity and sequence-specific DNA binding to promoters transcribed by RNA polymerase II. We propose that transcriptional misregulation of downstream genes by the absence of WRN protein contributes to the variable premature aging phenotypes of WS. There were no CpG sites showing significant differences in DNA methylation changes with age between WS patients and controls. Genes with both WS- and age-related methylation changes exhibited a constant offset of methylation between WRN-mutant patients and controls across the entire analyzed age range. WS-specific epigenetic signatures occur early in life and do not simply reflect an acceleration of normal epigenetic aging processes.}, language = {en} } @article{ElHajjDittrichBoecketal.2016, author = {El Hajj, Nady and Dittrich, Marcus and B{\"o}ck, Julia and Kraus, Theo F. J. and Nanda, Indrajit and M{\"u}ller, Tobias and Seidmann, Larissa and Tralau, Tim and Galetzka, Danuta and Schneider, Eberhard and Haaf, Thomas}, title = {Epigenetic dysregulation in the developing Down syndrome cortex}, series = {Epigenetics}, volume = {11}, journal = {Epigenetics}, number = {8}, doi = {10.1080/15592294.2016.1192736}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-191239}, pages = {563-578}, year = {2016}, abstract = {Using Illumina 450K arrays, 1.85\% of all analyzed CpG sites were significantly hypermethylated and 0.31\% hypomethylated in fetal Down syndrome (DS) cortex throughout the genome. The methylation changes on chromosome 21 appeared to be balanced between hypo- and hyper-methylation, whereas, consistent with prior reports, all other chromosomes showed 3-11times more hyper- than hypo-methylated sites. Reduced NRSF/REST expression due to upregulation of DYRK1A (on chromosome 21q22.13) and methylation of REST binding sites during early developmental stages may contribute to this genome-wide excess of hypermethylated sites. Upregulation of DNMT3L (on chromosome 21q22.4) could lead to de novo methylation in neuroprogenitors, which then persists in the fetal DS brain where DNMT3A and DNMT3B become downregulated. The vast majority of differentially methylated promoters and genes was hypermethylated in DS and located outside chromosome 21, including the protocadherin gamma (PCDHG) cluster on chromosome 5q31, which is crucial for neural circuit formation in the developing brain. Bisulfite pyrosequencing and targeted RNA sequencing showed that several genes of PCDHG subfamilies A and B are hypermethylated and transcriptionally downregulated in fetal DS cortex. Decreased PCDHG expression is expected to reduce dendrite arborization and growth in cortical neurons. Since constitutive hypermethylation of PCDHG and other genes affects multiple tissues, including blood, it may provide useful biomarkers for DS brain development and pharmacologic targets for therapeutic interventions.}, language = {en} } @article{MartratMaxwellTominagaetal.2011, author = {Martrat, Griselda and Maxwell, Christopher A. and Tominaga, Emiko and Porta-de-la-Riva, Montserrat and Bonifaci, N{\´u}ria and G{\´o}mez-Bald{\´o}, Laia and Bogliolo, Massimo and L{\´a}zaro, Conxi and Blanco, Ignacio and Brunet, Joan and Neveling, Kornelia and et al,}, title = {Exploring the link between MORF4L1 and risk of breast cancer}, series = {Breast Cancer Research}, volume = {13}, journal = {Breast Cancer Research}, number = {R40}, doi = {10.1186/bcr2862}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-169119}, pages = {1-14}, year = {2011}, abstract = {Introduction: Proteins encoded by Fanconi anemia (FA) and/or breast cancer (BrCa) susceptibility genes cooperate in a common DNA damage repair signaling pathway. To gain deeper insight into this pathway and its influence on cancer risk, we searched for novel components through protein physical interaction screens. Methods: Protein physical interactions were screened using the yeast two-hybrid system. Co-affinity purifications and endogenous co-immunoprecipitation assays were performed to corroborate interactions. Biochemical and functional assays in human, mouse and Caenorhabditis elegans models were carried out to characterize pathway components. Thirteen FANCD2-monoubiquitinylation-positive FA cell lines excluded for genetic defects in the downstream pathway components and 300 familial BrCa patients negative for BRCA1/2 mutations were analyzed for genetic mutations. Common genetic variants were genotyped in 9,573 BRCA1/2 mutation carriers for associations with BrCa risk. Results: A previously identified co-purifying protein with PALB2 was identified, MRG15 (MORF4L1 gene). Results in human, mouse and C. elegans models delineate molecular and functional relationships with BRCA2, PALB2, RAD51 and RPA1 that suggest a role for MRG15 in the repair of DNA double-strand breaks. Mrg15-deficient murine embryonic fibroblasts showed moderate sensitivity to g-irradiation relative to controls and reduced formation of Rad51 nuclear foci. Examination of mutants of MRG15 and BRCA2 C. elegans orthologs revealed phenocopy by accumulation of RPA-1 (human RPA1) nuclear foci and aberrant chromosomal compactions in meiotic cells. However, no alterations or mutations were identified for MRG15/MORF4L1 in unclassified FA patients and BrCa familial cases. Finally, no significant associations between common MORF4L1 variants and BrCa risk for BRCA1 or BRCA2 mutation carriers were identified: rs7164529, Ptrend = 0.45 and 0.05, P2df = 0.51 and 0.14, respectively; and rs10519219, Ptrend = 0.92 and 0.72, P2df = 0.76 and 0.07, respectively. Conclusions: While the present study expands on the role of MRG15 in the control of genomic stability, weak associations cannot be ruled out for potential low-penetrance variants at MORF4L1 and BrCa risk among BRCA2 mutation carriers.}, language = {en} } @article{RodriguezMariWilsonTitusetal.2011, author = {Rodr{\´i}guez-Mari, Adriana and Wilson, Catherine and Titus, Tom A. and Canestro, Cristian and BreMiller, Ruth A. and Yan, Yi-Lin and Nanda, Indrajit and Johnston, Adam and Kanki, John P. and Gray, Erin M. and He, Xinjun and Spitsbergen, Jan and Schindler, Detlev and Postlethwait, John H.}, title = {Roles of brca2 (fancd1) in Oocyte Nuclear Architecture, Gametogenesis, Gonad Tumors, and Genome Stability in Zebrafish}, series = {PLoS Genetics}, volume = {7}, journal = {PLoS Genetics}, number = {3}, doi = {10.1371/journal.pone.0026377}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-142285}, pages = {e1001357}, year = {2011}, abstract = {Functional near-infrared spectroscopy (fNIRS) is an established optical neuroimaging method for measuring functional hemodynamic responses to infer neural activation. However, the impact of individual anatomy on the sensitivity of fNIRS measuring hemodynamics within cortical gray matter is still unknown. By means of Monte Carlo simulations and structural MRI of 23 healthy subjects (mean age: (25.0 +/- 2.8) years), we characterized the individual distribution of tissue-specific NIR-light absorption underneath 24 prefrontal fNIRS channels. We, thereby, investigated the impact of scalp-cortex distance (SCD), frontal sinus volume as well as sulcal morphology on gray matter volumes (V(gray)) traversed by NIR-light, i.e. anatomy-dependent fNIRS sensitivity. The NIR-light absorption between optodes was distributed describing a rotational ellipsoid with a mean penetration depth of (23.6 +/- 0.7) mm considering the deepest 5\% of light. Of the detected photon packages scalp and bone absorbed (96.4 +/- 9: 7)\% and V(gray) absorbed (3.1 +/- 1.8)\% of the energy. The mean V(gray) volume (1.1 +/- 0.4)cm(3) was negatively correlated (r = - .76) with the SCD and frontal sinus volume (r = - .57) and was reduced by 41.5\% in subjects with relatively large compared to small frontal sinus. Head circumference was significantly positively correlated with the mean SCD (r = .46) and the traversed frontal sinus volume (r = .43). Sulcal morphology had no significant impact on V(gray). Our findings suggest to consider individual SCD and frontal sinus volume as anatomical factors impacting fNIRS sensitivity. Head circumference may represent a practical measure to partly control for these sources of error variance.}, language = {en} } @article{WeisSchoenVictoretal.2011, author = {Weis, Eva and Schoen, Holger and Victor, Anja and Spix, Claudia and Ludwig, Marco and Schneider-Raetzke, Brigitte and Kohlschmidt, Nicolai and Bartsch, Oliver and Gerhold-Ay, Aslihan and Boehm, Nils and Grus, Franz and Haaf, Thomas and Galetzka, Danuta}, title = {Reduced mRNA and Protein Expression of the Genomic Caretaker RAD9A in Primary Fibroblasts of Individuals with Childhood and Independent Second Cancer}, series = {PLoS ONE}, volume = {6}, journal = {PLoS ONE}, number = {10}, doi = {10.1371/journal.pone.0025750}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-141838}, pages = {e25750}, year = {2011}, abstract = {Background: The etiology of secondary cancer in childhood cancer survivors is largely unclear. Exposure of normal somatic cells to radiation and/or chemotherapy can damage DNA and if not all DNA lesions are properly fixed, the mis-repair may lead to pathological consequences. It is plausible to assume that genetic differences, i.e. in the pathways responsible for cell cycle control and DNA repair, play a critical role in the development of secondary cancer. Methodology/Findings: To identify factors that may influence the susceptibility for second cancer formation, we recruited 20 individuals who survived a childhood malignancy and then developed a second cancer as well as 20 carefully matched control individuals with childhood malignancy but without a second cancer. By antibody microarrays, we screened primary fibroblasts of matched patients for differences in the amount of representative DNA repair-associated proteins. We found constitutively decreased levels of RAD9A and several other DNA repair proteins in two-cancer patients, compared to one-cancer patients. The RAD9A protein level increased in response to DNA damage, however to a lesser extent in the two-cancer patients. Quantification of mRNA expression by real-time RT PCR revealed lower RAD9A mRNA levels in both untreated and 1 Gy gamma-irradiated cells of two-cancer patients. Conclusions/Significance: Collectively, our results support the idea that modulation of RAD9A and other cell cycle arrest and DNA repair proteins contribute to the risk of developing a second malignancy in childhood cancer patients.}, language = {en} } @article{KuhtzSchneiderElHajjetal.2014, author = {Kuhtz, Juliane and Schneider, Eberhard and El Hajj, Nady and Zimmermann, Lena and Fust, Olga and Linek, Bartosz and Seufert, Rudolf and Hahn, Thomas and Schorsch, Martin and Haaf, Thomas}, title = {Epigenetic heterogeneity of developmentally important genes in human sperm: Implications for assisted reproduction outcome}, series = {Epigenetics}, volume = {9}, journal = {Epigenetics}, number = {12}, doi = {10.4161/15592294.2014.988063}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-150261}, pages = {1648-1658}, year = {2014}, abstract = {The molecular basis of male infertility is poorly understood, the majority of cases remaining unsolved. The association of aberrant sperm DNA methylation patterns and compromised semen parameters suggests that disturbances in male germline epigenetic reprogramming contribute to this problem. So far there are only few data on the epigenetic heterogeneity of sperm within a given sample and how to select the best sperm for successful infertility treatment. Limiting dilution bisulfite sequencing of small pools of sperm from fertile donors did not reveal significant differences in the occurrence of abnormal methylation imprints between sperm with and without morphological abnormalities. Intracytoplasmic morphologically selected sperm injection was not associated with an improved epigenetic quality, compared to standard intracytoplasmatic sperm injection. Deep bisulfite sequencing (DBS) of 2 imprinted and 2 pluripotency genes in sperm from men attending a fertility center showed that in both samples with normozoospermia and oligoasthenoteratozoospermia (OAT) the vast majority of sperm alleles was normally (de)methylated and the percentage of epimutations (allele methylation errors) was generally low (<1\%). However, DBS allowed one to identify and quantify these rare epimutations with high accuracy. Sperm samples not leading to a pregnancy, in particular in the OAT group, had significantly more epimutations in the paternally methylated GTL2 gene than samples leading to a live birth. All 13 normozoospermic and 13 OAT samples leading to a child had <1\% GTL2 epimutations, whereas one (7\%) of 14 normozoospermic and 7 (50\%) of 14 OAT samples without pregnancy displayed 1-14\% GTL2 epimutations.}, language = {en} } @article{BlancoKuchenbaeckerCuadrasetal.2015, author = {Blanco, Ignacio and Kuchenbaecker, Karoline and Cuadras, Daniel and Wang, Xianshu and Barrowdale, Daniel and Ruiz de Garibay, Gorka and Librado, Pablo and Sanchez-Gracia, Alejandro and Rozas, Julio and Bonifaci, N{\´u}ria and McGuffog, Lesley and Pankratz, Vernon S. and Islam, Abul and Mateo, Francesca and Berenguer, Antoni and Petit, Anna and Catal{\`a}, Isabel and Brunet, Joan and Feliubadal{\´o}, Lidia and Tornero, Eva and Ben{\´i}tez, Javier and Osorio, Ana and Ram{\´o}n y Cajal, Teresa and Nevanlinna, Heli and Aittom{\"a}ki, Kristina and Arun, Banu K. and Toland, Amanda E. and Karlan, Beth Y. and Walsh, Christine and Lester, Jenny and Greene, Mark H. and Mai, Phuong L. and Nussbaum, Robert L. and Andrulis, Irene L. and Domchek, Susan M. and Nathanson, Katherine L. and Rebbeck, Timothy R. and Barkardottir, Rosa B. and Jakubowska, Anna and Lubinski, Jan and Durda, Katarzyna and Jaworska-Bieniek, Katarzyna and Claes, Kathleen and Van Maerken, Tom and D{\´i}ez, Orland and Hansen, Thomas V. and J{\o}nson, Lars and Gerdes, Anne-Marie and Ejlertsen, Bent and De la Hoya, Miguel and Cald{\´e}s, Trinidad and Dunning, Alison M. and Oliver, Clare and Fineberg, Elena and Cook, Margaret and Peock, Susan and McCann, Emma and Murray, Alex and Jacobs, Chris and Pichert, Gabriella and Lalloo, Fiona and Chu, Carol and Dorkins, Huw and Paterson, Joan and Ong, Kai-Ren and Teixeira, Manuel R. and Hogervorst, Frans B. L. and Van der Hout, Annemarie H. and Seynaeve, Caroline and Van der Luijt, Rob B. and Ligtenberg, Marjolijn J. L. and Devilee, Peter and Wijnen, Juul T. and Rookus, Matti A. and Meijers-Heijboer, Hanne E. J. and Blok, Marinus J. and Van den Ouweland, Ans M. W. and Aalfs, Cora M. and Rodriguez, Gustavo C. and Phillips, Kelly-Anne A. and Piedmonte, Marion and Nerenstone, Stacy R. and Bae-Jump, Victoria L. and O'Malley, David M. and Schmutzler, Rita K. and Wappenschmidt, Barbara and Rhiem, Kerstin and Engel, Christoph and Meindl, Alfons and Ditsch, Nina and Arnold, Norbert and Plendl, Hansjoerg J. and Niederacher, Dieter and Sutter, Christian and Wang-Gohrke, Shan and Steinemann, Doris and Preisler-Adams, Sabine and Kast, Karin and Varon-Mateeva, Raymonda and Gehrig, Andrea and Bojesen, Anders and Pedersen, Inge Sokilde and Sunde, Lone and Birk Jensen, Uffe and Thomassen, Mads and Kruse, Torben A. and Foretova, Lenka and Peterlongo, Paolo and Bernard, Loris and Peissel, Bernard and Scuvera, Giulietta and Manoukian, Siranoush and Radice, Paolo and Ottini, Laura and Montagna, Marco and Agata, Simona and Maugard, Christine and Simard, Jacques and Soucy, Penny and Berger, Andreas and Fink-Retter, Anneliese and Singer, Christian F. and Rappaport, Christine and Geschwantler-Kaulich, Daphne and Tea, Muy-Kheng and Pfeiler, Georg and John, Esther M. and Miron, Alex and Neuhausen, Susan L. and Terry, Mary Beth and Chung, Wendy K. and Daly, Mary B. and Goldgar, David E. and Janavicius, Ramunas and Dorfling, Cecilia M. and Van Rensburg, Elisabeth J. and Fostira, Florentia and Konstantopoulou, Irene and Garber, Judy and Godwin, Andrew K. and Olah, Edith and Narod, Steven A. and Rennert, Gad and Paluch, Shani Shimon and Laitman, Yael and Friedman, Eitan and Liljegren, Annelie and Rantala, Johanna and Stenmark-Askmalm, Marie and Loman, Niklas and Imyanitov, Evgeny N. and Hamann, Ute and Spurdle, Amanda B. and Healey, Sue and Weitzel, Jeffrey N. and Herzog, Josef and Margileth, David and Gorrini, Chiara and Esteller, Manel and G{\´o}mez, Antonio and Sayols, Sergi and Vidal, Enrique and Heyn, Holger and Stoppa-Lyonnet, Dominique and L{\´e}on{\´e}, Melanie and Barjhoux, Laure and Fassy-Colcombet, Marion and Pauw, Antoine de and Lasset, Christine and Fert Ferrer, Sandra and Castera, Laurent and Berthet, Pascaline and Cornelis, Fran{\c{c}}ois and Bignon, Yves-Jean and Damiola, Francesca and Mazoyer, Sylvie and Sinilnikova, Olga M. and Maxwell, Christopher A. and Vijai, Joseph and Robson, Mark and Kauff, Noah and Corines, Marina J. and Villano, Danylko and Cunningham, Julie and Lee, Adam and Lindor, Noralane and L{\´a}zaro, Conxi and Easton, Douglas F. and Offit, Kenneth and Chenevix-Trench, Georgia and Couch, Fergus J. and Antoniou, Antonis C. and Pujana, Miguel Angel}, title = {Assessing associations between the AURKA-HMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers}, series = {PLoS ONE}, volume = {10}, journal = {PLoS ONE}, number = {4}, doi = {10.1371/journal.pone.0120020}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-143469}, pages = {e0120020}, year = {2015}, abstract = {While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95\% confidence interval (CI) 1.04 - 1.15, p = 1.9 x 10\(^{-4}\) (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95\% CI 1.03 - 1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted p\(_{interaction}\) values > 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients' survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers.}, language = {en} } @article{SchneiderDittrichBoecketal.2016, author = {Schneider, Eberhard and Dittrich, Marcus and B{\"o}ck, Julia and Nanda, Indrajit and M{\"u}ller, Tobias and Seidmann, Larissa and Tralau, Tim and Galetzka, Danuta and El Hajj, Nady and Haaf, Thomas}, title = {CpG sites with continuously increasing or decreasing methylation from early to late human fetal brain development}, series = {Gene}, volume = {592}, journal = {Gene}, number = {1}, doi = {10.1016/j.gene.2016.07.058}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-186936}, pages = {110-118}, year = {2016}, abstract = {Normal human brain development is dependent on highly dynamic epigenetic processes for spatial and temporal gene regulation. Recent work identified wide-spread changes in DNA methylation during fetal brain development. We profiled CpG methylation in frontal cortex of 27 fetuses from gestational weeks 12-42, using Illumina 450K methylation arrays. Sites showing genome-wide significant correlation with gestational age were compared to a publicly available data set from gestational weeks 3-26. Altogether, we identified 2016 matching developmentally regulated differentially methylated positions (m-dDMPs): 1767 m-dDMPs were hypermethylated and 1149 hypomethylated during fetal development. M-dDMPs are underrepresented in CpG islands and gene promoters, and enriched in gene bodies. They appear to cluster in certain chromosome regions. M-dDMPs are significantly enriched in autism-associated genes and CpGs. Our results promote the idea that reduced methylation dynamics during fetal brain development may predispose to autism. In addition, m-dDMPs are enriched in genes with human-specific brain expression patterns and/or histone modifications. Collectively, we defined a subset of dDMPs exhibiting constant methylation changes from early to late pregnancy. The same epigenetic mechanisms involving methylation changes in cis-regulatory regions may have been adopted for human brain evolution and ontogeny.}, language = {en} } @article{VigoritoKuchenbaeckerBeesleyetal.2016, author = {Vigorito, Elena and Kuchenbaecker, Karoline B. and Beesley, Jonathan and Adlard, Julian and Agnarsson, Bjarni A. and Andrulis, Irene L. and Arun, Banu K. and Barjhoux, Laure and Belotti, Muriel and Benitez, Javier and Berger, Andreas and Bojesen, Anders and Bonanni, Bernardo and Brewer, Carole and Caldes, Trinidad and Caligo, Maria A. and Campbell, Ian and Chan, Salina B. and Claes, Kathleen B. M. and Cohn, David E. and Cook, Jackie and Daly, Mary B. and Damiola, Francesca and Davidson, Rosemarie and de Pauw, Antoine and Delnatte, Capucine and Diez, Orland and Domchek, Susan M. and Dumont, Martine and Durda, Katarzyna and Dworniczak, Bernd and Easton, Douglas F. and Eccles, Diana and Ardnor, Christina Edwinsdotter and Eeles, Ros and Ejlertsen, Bent and Ellis, Steve and Evans, D. Gareth and Feliubadalo, Lidia and Fostira, Florentia and Foulkes, William D. and Friedman, Eitan and Frost, Debra and Gaddam, Pragna and Ganz, Patricia A. and Garber, Judy and Garcia-Barberan, Vanesa and Gauthier-Villars, Marion and Gehrig, Andrea and Gerdes, Anne-Marie and Giraud, Sophie and Godwin, Andrew K. and Goldgar, David E. and Hake, Christopher R. and Hansen, Thomas V. O. and Healey, Sue and Hodgson, Shirley and Hogervorst, Frans B. L. and Houdayer, Claude and Hulick, Peter J. and Imyanitov, Evgeny N. and Isaacs, Claudine and Izatt, Louise and Izquierdo, Angel and Jacobs, Lauren and Jakubowska, Anna and Janavicius, Ramunas and Jaworska-Bieniek, Katarzyna and Jensen, Uffe Birk and John, Esther M. and Vijai, Joseph and Karlan, Beth Y. and Kast, Karin and Khan, Sofia and Kwong, Ava and Laitman, Yael and Lester, Jenny and Lesueur, Fabienne and Liljegren, Annelie and Lubinski, Jan and Mai, Phuong L. and Manoukian, Siranoush and Mazoyer, Sylvie and Meindl, Alfons and Mensenkamp, Arjen R. and Montagna, Marco and Nathanson, Katherine L. and Neuhausen, Susan L. and Nevanlinna, Heli and Niederacher, Dieter and Olah, Edith and Olopade, Olufunmilayo I. and Ong, Kai-ren and Osorio, Ana and Park, Sue Kyung and Paulsson-Karlsson, Ylva and Pedersen, Inge Sokilde and Peissel, Bernard and Peterlongo, Paolo and Pfeiler, Georg and Phelan, Catherine M. and Piedmonte, Marion and Poppe, Bruce and Pujana, Miquel Angel and Radice, Paolo and Rennert, Gad and Rodriguez, Gustavo C. and Rookus, Matti A. and Ross, Eric A. and Schmutzler, Rita Katharina and Simard, Jacques and Singer, Christian F. and Slavin, Thomas P. and Soucy, Penny and Southey, Melissa and Steinemann, Doris and Stoppa-Lyonnet, Dominique and Sukiennicki, Grzegorz and Sutter, Christian and Szabo, Csilla I. and Tea, Muy-Kheng and Teixeira, Manuel R. and Teo, Soo-Hwang and Terry, Mary Beth and Thomassen, Mads and Tibiletti, Maria Grazia and Tihomirova, Laima and Tognazzo, Silvia and van Rensburg, Elizabeth J. and Varesco, Liliana and Varon-Mateeva, Raymonda and Vratimos, Athanassios and Weitzel, Jeffrey N. and McGuffog, Lesley and Kirk, Judy and Toland, Amanda Ewart and Hamann, Ute and Lindor, Noralane and Ramus, Susan J. and Greene, Mark H. and Couch, Fergus J. and Offit, Kenneth and Pharoah, Paul D. P. and Chenevix-Trench, Georgia and Antoniou, Antonis C.}, title = {Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers}, series = {PLoS ONE}, volume = {11}, journal = {PLoS ONE}, number = {7}, doi = {10.1371/journal.pone.0158801}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-166869}, pages = {e0158801}, year = {2016}, abstract = {Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA1 and BRCA 2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95\%CI: 0.68 to 0.79, p-value 2× 10-16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95\%CI: 0.59 to 0.80, p-value 1.0 × 10-6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population.}, language = {en} } @article{SchneiderPliushchElHajjetal.2010, author = {Schneider, Eberhard and Pliushch, Galyna and El Hajj, Nady and Galetzka, Danuta and Puhl, Alexander and Schorsch, Martin and Frauenknecht, Katrin and Riepert, Thomas and Tresch, Achim and Mueller, Annette M. and Coerdt, Wiltrud and Zechner, Ulrich and Haaf, Thomas}, title = {Spatial, temporal and interindividual epigenetic variation of functionally important DNA methylation patterns}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-68371}, year = {2010}, abstract = {DNA methylation is an epigenetic modification that plays an important role in gene regulation. It can be influenced by stochastic events, environmental factors and developmental programs. However, little is known about the natural variation of genespecific methylation patterns. In this study, we performed quantitative methylation analyses of six differentially methylated imprinted genes (H19, MEG3, LIT1, NESP55, PEG3 and SNRPN), one hypermethylated pluripotency gene (OCT4) and one hypomethylated tumor suppressor gene (APC) in chorionic villus, fetal and adult cortex, and adult blood samples. Both average methylation level and range of methylation variation depended on the gene locus, tissue type and/or developmental stage. We found considerable variability of functionally important methylation patterns among unrelated healthy individuals and a trend toward more similar methylation levels in monozygotic twins than in dizygotic twins. Imprinted genes showed relatively little methylation changes associated with aging in individuals who are >25 years. The relative differences in methylation among neighboring CpGs in the generally hypomethylated APC promoter may not only reflect stochastic fluctuations but also depend on the tissue type. Our results are consistent with the view that most methylation variation may arise after fertilization, leading to epigenetic mosaicism.}, subject = {Medizin}, language = {en} } @article{WeisSchoenVictoretal.2011, author = {Weis, Eva and Schoen, Holger and Victor, Anja and Spix, Claudia and Ludwig, Marco and Schneider-Raetzke, Brigitte and Kohlschmidt, Nicolai and Bartsch, Oliver and Gerhold-Ay, Aslihan and Boehm, Nils and Grus, Franz and Haaf, Thomas and Galetzka, Danuta}, title = {Reduced mRNA and Protein Expression of the Genomic Caretaker RAD9A in Primary Fibroblasts of Individuals with Childhood and Independent Second Cancer}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-74777}, year = {2011}, abstract = {Background: The etiology of secondary cancer in childhood cancer survivors is largely unclear. Exposure of normal somatic cells to radiation and/or chemotherapy can damage DNA and if not all DNA lesions are properly fixed, the mis-repair may lead to pathological consequences. It is plausible to assume that genetic differences, i.e. in the pathways responsible for cell cycle control and DNA repair, play a critical role in the development of secondary cancer. Methodology/Findings: To identify factors that may influence the susceptibility for second cancer formation, we recruited 20 individuals who survived a childhood malignancy and then developed a second cancer as well as 20 carefully matched control individuals with childhood malignancy but without a second cancer. By antibody microarrays, we screened primary fibroblasts of matched patients for differences in the amount of representative DNA repair-associated proteins. We found constitutively decreased levels of RAD9A and several other DNA repair proteins in two-cancer patients, compared to onecancer patients. The RAD9A protein level increased in response to DNA damage, however to a lesser extent in the twocancer patients. Quantification of mRNA expression by real-time RT PCR revealed lower RAD9A mRNA levels in both untreated and 1 Gy c-irradiated cells of two-cancer patients. Conclusions/Significance: Collectively, our results support the idea that modulation of RAD9A and other cell cycle arrest and DNA repair proteins contribute to the risk of developing a second malignancy in childhood cancer patients.}, subject = {Medizin}, language = {en} } @article{GavvovidisRostTrimbornetal.2012, author = {Gavvovidis, Ioannis and Rost, Isabell and Trimborn, Marc and Kaiser, Frank J. and Purps, Josephine and Wiek, Konstanze and Haneberg, Helmut and Neitzel, Heidemarie and Schindler, Detlev}, title = {A Novel MCPH1 Isoform Complements the Defective Chromosome Condensation of Human MCPH1-Deficient Cells}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-75050}, year = {2012}, abstract = {Biallelic mutations in MCPH1 cause primary microcephaly (MCPH) with the cellular phenotype of defective chromosome condensation. MCPH1 encodes a multifunctional protein that notably is involved in brain development, regulation of chromosome condensation, and DNA damage response. In the present studies, we detected that MCPH1 encodes several distinct transcripts, including two major forms: full-length MCPH1 (MCPH1-FL) and a second transcript lacking the six 39 exons (MCPH1De9-14). Both variants show comparable tissue-specific expression patterns, demonstrate nuclear localization that is mediated independently via separate NLS motifs, and are more abundant in certain fetal than adult organs. In addition, the expression of either isoform complements the chromosome condensation defect found in genetically MCPH1-deficient or MCPH1 siRNA-depleted cells, demonstrating a redundancy of both MCPH1 isoforms for the regulation of chromosome condensation. Strikingly however, both transcripts are regulated antagonistically during cell-cycle progression and there are functional differences between the isoforms with regard to the DNA damage response; MCPH1-FL localizes to phosphorylated H2AX repair foci following ionizing irradiation, while MCPH1De9-14 was evenly distributed in the nucleus. In summary, our results demonstrate here that MCPH1 encodes different isoforms that are differentially regulated at the transcript level and have different functions at the protein level.}, subject = {MCPH1}, language = {en} } @article{MeierSchindler2011, author = {Meier, Daniel and Schindler, Detlev}, title = {Fanconi Anemia Core Complex Gene Promoters Harbor Conserved Transcription Regulatory Elements}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-68917}, year = {2011}, abstract = {The Fanconi anemia (FA) gene family is a recent addition to the complex network of proteins that respond to and repair certain types of DNA damage in the human genome. Since little is known about the regulation of this novel group of genes at the DNA level, we characterized the promoters of the eight genes (FANCA, B, C, E, F, G, L and M) that compose the FA core complex. The promoters of these genes show the characteristic attributes of housekeeping genes, such as a high GC content and CpG islands, a lack of TATA boxes and a low conservation. The promoters functioned in a monodirectional way and were, in their most active regions, comparable in strength to the SV40 promoter in our reporter plasmids. They were also marked by a distinctive transcriptional start site (TSS). In the 59 region of each promoter, we identified a region that was able to negatively regulate the promoter activity in HeLa and HEK 293 cells in isolation. The central and 39 regions of the promoter sequences harbor binding sites for several common and rare transcription factors, including STAT, SMAD, E2F, AP1 and YY1, which indicates that there may be cross-connections to several established regulatory pathways. Electrophoretic mobility shift assays and siRNA experiments confirmed the shared regulatory responses between the prominent members of the TGF-b and JAK/STAT pathways and members of the FA core complex. Although the promoters are not well conserved, they share region and sequence specific regulatory motifs and transcription factor binding sites (TBFs), and we identified a bi-partite nature to these promoters. These results support a hypothesis based on the co-evolution of the FA core complex genes that was expanded to include their promoters.}, subject = {Fanconi-An{\"a}mie}, language = {en} } @article{FaragFroehlerOexleetal.2013, author = {Farag, Heba Gamal and Froehler, Sebastian and Oexle, Konrad and Ravindran, Ethiraj and Schindler, Detlev and Staab, Timo and Huebner, Angela and Kraemer, Nadine and Chen, Wei and Kaindl, Angela M.}, title = {Abnormal centrosome and spindle morphology in a patient with autosomal recessive primary microcephaly type 2 due to compound heterozygous WDR62 gene mutation}, series = {Orphanet Journal of Rare Diseases}, volume = {8}, journal = {Orphanet Journal of Rare Diseases}, number = {178}, issn = {1750-1172}, doi = {10.1186/1750-1172-8-178}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-123505}, year = {2013}, abstract = {Background: Autosomal recessive primary microcephaly (MCPH) is a rare neurodevelopmental disease with severe microcephaly at birth due to a pronounced reduction in brain volume and intellectual disability. Biallelic mutations in the WD repeat-containing protein 62 gene WDR62 are the genetic cause of MCPH2. However, the exact underlying pathomechanism of MCPH2 remains to be clarified. Methods/results: We characterized the clinical, radiological, and cellular features that add to the human MCPH2 phenotype. Exome sequencing followed by Sanger sequencing in a German family with two affected daughters with primary microcephaly revealed in the index patient the compound heterozygous mutations c. 1313G>A (p.R438H) / c.2864-2867delACAG (p.D955Afs*112) of WDR62, the second of which is novel. Radiological examination displayed small frontal lobes, corpus callosum hypoplasia, simplified hippocampal gyration, and cerebellar hypoplasia. We investigated the cellular phenotype in patient-derived lymphoblastoid cells and compared it with that of healthy female controls. WDR62 expression in the patient's immortalized lymphocytes was deranged, and mitotic spindle defects as well as abnormal centrosomal protein localization were apparent. Conclusion: We propose that a disruption of centrosome integrity and/or spindle organization may play an important role in the development of microcephaly in MCPH2.}, language = {en} } @article{SchreiberSchneideratKressetal.2013, author = {Schreiber, Olivia and Schneiderat, Peter and Kress, Wolfram and Rautenstrauss, Bernd and Senderek, Jan and Schoser, Bendikt and Walter, Maggie C.}, title = {Facioscapulohumeral muscular dystrophy and Charcot-Marie-Tooth neuropathy 1A-evidence for "double trouble" overlapping syndromes}, series = {BMC Medical Genetics}, volume = {14}, journal = {BMC Medical Genetics}, number = {92}, issn = {1471-2350}, doi = {10.1186/1471-2350-14-92}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-121963}, year = {2013}, abstract = {Background: We report on a patient with genetically confirmed overlapping diagnoses of CMT1A and FSHD. This case adds to the increasing number of unique patients presenting with atypical phenotypes, particularly in FSHD. Even if a mutation in one disease gene has been found, further genetic testing might be warranted in cases with unusual clinical presentation. Case presentation: The reported 53 years old male patient suffered from walking difficulties and foot deformities first noticed at age 20. Later on, he developed scapuloperoneal and truncal muscle weakness, along with atrophy of the intrinsic hand and foot muscles, pes cavus, claw toes and a distal symmetric hypoesthesia. Motor nerve conduction velocities were reduced to 20 m/s in the upper extremities, and not educible in the lower extremities, sensory nerve conduction velocities were not attainable. Electromyography showed both, myopathic and neurogenic changes. A muscle biopsy taken from the tibialis anterior muscle showed a mild myopathy with some neurogenic findings and hypertrophic type 1 fibers. Whole-body muscle MRI revealed severe changes in the lower leg muscles, tibialis anterior and gastrocnemius muscles were highly replaced by fatty tissue. Additionally, fatty degeneration of shoulder girdle and straight back muscles, and atrophy of dorsal upper leg muscles were seen. Taken together, the presenting features suggested both, a neuropathy and a myopathy. Patient's family history suggested an autosomal dominant inheritance. Molecular testing revealed both, a hereditary motor and sensory neuropathy type 1A (HMSN1A, also called Charcot-Marie-Tooth neuropathy 1A, CMT1A) due to a PMP22 gene duplication and facioscapulohumeral muscular dystrophy (FSHD) due to a partial deletion of the D4Z4 locus (19 kb). Conclusion: Molecular testing in hereditary neuromuscular disorders has led to the identification of an increasing number of atypical phenotypes. Nevertheless, finding the right diagnosis is crucial for the patient in order to obtain adequate medical care and appropriate genetic counseling, especially in the background of arising curative therapies.}, language = {en} } @article{SchrautJakobWeidneretal.2014, author = {Schraut, K. G. and Jakob, S. B. and Weidner, M. T. and Schmitt, A. G. and Scholz, C. J. and Strekalova, T. and El Hajj, N. and Eijssen, L. M. T. and Domschke, K. and Reif, A. and Haaf, T. and Ortega, G. and Steinbusch, H. W. M. and Lesch, K. P. and Van den Hove, D. L.}, title = {Prenatal stress-induced programming of genome-wide promoter DNA methylation in 5-HTT-deficient mice}, series = {Translational Psychiatry}, volume = {4}, journal = {Translational Psychiatry}, doi = {10.1038/tp.2014.107}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-119199}, pages = {e473}, year = {2014}, abstract = {The serotonin transporter gene (5-HTT/SLC6A4)-linked polymorphic region has been suggested to have a modulatory role in mediating effects of early-life stress exposure on psychopathology rendering carriers of the low-expression short (s)-variant more vulnerable to environmental adversity in later life. The underlying molecular mechanisms of this gene-by-environment interaction are not well understood, but epigenetic regulation including differential DNA methylation has been postulated to have a critical role. Recently, we used a maternal restraint stress paradigm of prenatal stress (PS) in 5-HTT-deficient mice and showed that the effects on behavior and gene expression were particularly marked in the hippocampus of female 5-Htt+/- offspring. Here, we examined to which extent these effects are mediated by differential methylation of DNA. For this purpose, we performed a genome-wide hippocampal DNA methylation screening using methylated-DNA immunoprecipitation (MeDIP) on Affymetrix GeneChip Mouse Promoter 1.0 R arrays. Using hippocampal DNA from the same mice as assessed before enabled us to correlate gene-specific DNA methylation, mRNA expression and behavior. We found that 5-Htt genotype, PS and their interaction differentially affected the DNA methylation signature of numerous genes, a subset of which showed overlap with the expression profiles of the corresponding transcripts. For example, a differentially methylated region in the gene encoding myelin basic protein (Mbp) was associated with its expression in a 5-Htt-, PS- and 5-Htt × PS-dependent manner. Subsequent fine-mapping of this Mbp locus linked the methylation status of two specific CpG sites to Mbp expression and anxiety-related behavior. In conclusion, hippocampal DNA methylation patterns and expression profiles of female prenatally stressed 5-Htt+/- mice suggest that distinct molecular mechanisms, some of which are promoter methylation-dependent, contribute to the behavioral effects of the 5-Htt genotype, PS exposure and their interaction.}, language = {en} } @article{LachaudCastorHainetal.2014, author = {Lachaud, Christophe and Castor, Dennis and Hain, Karolina and Mu{\~n}oz, Ivan and Wilson, Jamie and MacArtney, Thomas J. and Schindler, Detlev and Rouse, John}, title = {Distinct functional roles for the two SLX4 ubiquitin-binding UBZ domains mutated in Fanconi anemia}, series = {Journal of Cell Science}, volume = {127}, journal = {Journal of Cell Science}, number = {13}, issn = {1477-9137}, doi = {10.1242/jcs.146167}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-120908}, pages = {2811-7}, year = {2014}, abstract = {Defects in SLX4, a scaffold for DNA repair nucleases, cause Fanconi anemia due to defective repair of inter-strand DNA crosslinks (ICLs). Some FA patients have an SLX4 deletion removing two tandem UBZ4-type ubiquitin-binding domains, implicated in protein recruitment to sites of DNA damage. Here we show that human SLX4 is recruited to sites of ICL induction but the UBZ-deleted form of SLX4 in cells from FA patients is not. SLX4 recruitment does not require ubiquitination of FANCD2, or the E3 ligases RNF8, RAD18 and BRCA1. We show that the first (UBZ-1), but not the second UBZ domain of SLX4 binds to ubiquitin polymers with a preference for K63-linked chains. Furthermore, UBZ-1 is required for SLX4 recruitment to ICL sites, and for efficient ICL repair in murine fibroblasts. SLX4 UBZ-2 domain does not bind ubiquitin in vitro or contribute to ICL repair, but it is required for resolution of Holliday junctions in vivo. These data shed light on SLX4 recruitment, and suggest that there remain to be identified ubiquitinated ligands and E3 ligases critical for ICL repair.}, language = {en} } @article{CouchWangMcGuffogetal.2013, author = {Couch, Fergus J. and Wang, Xianshu and McGuffog, Lesley and Lee, Andrew and Olswold, Curtis and Kuchenbaecker, Karoline B. and Soucy, Penny and Fredericksen, Zachary and Barrowdale, Daniel and Dennis, Joe and Gaudet, Mia M. and Dicks, Ed and Kosel, Matthew and Healey, Sue and Sinilnikova, Olga M. and Lee, Adam and Bacot, Fran{\c{c}}ios and Vincent, Daniel and Hogervorst, Frans B. L. and Peock, Susan and Stoppa-Lyonnet, Dominique and Jakubowska, Anna and Radice, Paolo and Schmutzler, Rita Katharina and Domchek, Susan M. and Piedmonte, Marion and Singer, Christian F. and Friedman, Eitan and Thomassen, Mads and Hansen, Thomas V. O. and Neuhausen, Susan L. and Szabo, Csilla I. and Blanco, Ingnacio and Greene, Mark H. and Karlan, Beth Y. and Garber, Judy and Phelan, Catherine M. and Weitzel, Jeffrey N. and Montagna, Marco and Olah, Edith and Andrulis, Irene L. and Godwin, Andrew K. and Yannoukakos, Drakoulis and Goldgar, David E. and Caldes, Trinidad and Nevanlinna, Heli and Osorio, Ana and Terry, Mary Beth and Daly, Mary B. and van Rensburg, Elisabeth J. and Hamann, Ute and Ramus, Susan J. and Toland, Amanda Ewart and Caligo, Maria A. and Olopade, Olufunmilayo I. and Tung, Nadine and Claes, Kathleen and Beattie, Mary S. and Southey, Melissa C. and Imyanitov, Evgeny N. and Tischkowitz, Marc and Janavicius, Ramunas and John, Esther M. and Kwong, Ava and Diez, Orland and Kwong, Ava and Balma{\~n}a, Judith and Barkardottir, Rosa B. and Arun, Banu K. and Rennert, Gad and Teo, Soo-Hwang and Ganz, Patricia A. and Campbell, Ian and van der Hout, Annemarie H. and van Deurzen, Carolien H. M. and Seynaeve, Caroline and Garcia, Encarna B. G{\´o}mez and van Leeuwen, Flora E. and Meijers-Heijboer, Hanne E. J. and Gille, Johannes J. P. and Ausems, Magreet G. E. M. and Blok, Marinus J. and Ligtenberg, Marjolinjin J. L. and Rookus, Matti A. and Devilee, Peter and Verhoef, Senno and van Os, Theo A. M. and Wijnen, Juul T. and Frost, Debra and Ellis, Steve and Fineberg, Elena and Platte, Radke and Evans, D. Gareth and Izatt, Luise and Eeles, Rosalind A. and Adlard, Julian and Eccles, Diana M. and Cook, Jackie and Brewer, Carole and Douglas, Fiona and Hodgson, Shirley and Morrison, Patrick J. and Side, Lucy E. and Donaldson, Alan and Houghton, Catherine and Rogers, Mark T. and Dorkins, Huw and Eason, Jacqueline and Gregory, Helen and McCann, Emma and Murray, Alex and Calender, Alain and Hardouin, Agn{\`e}s and Berthet, Pascaline and Delnatte, Capucine and Nogues, Catherine and Lasset, Christine and Houdayer, Claude and Leroux,, Dominique and Rouleau, Etienne and Prieur, Fabienne and Damiola, Francesca and Sobol, Hagay and Coupier, Isabelle and Venat-Bouvet, Laurence and Castera, Laurent and Gauthier-Villars, Marion and L{\´e}on{\´e}, M{\´e}lanie and Pujol, Pascal and Mazoyer, Sylvie and Bignon, Yves-Jean and Zlowocka-Perlowska, Elzbieta and Gronwald, Jacek and Lubinski,, Jan and Durda, Katarzyna and Jaworska, Katarzyna and Huzarski, Tomasz and Spurdle, Amanda B. and Viel, Alessandra and Peissel, Bernhard and Bonanni, Bernardo and Melloni, Guilia and Ottini, Laura and Papi, Laura and Varesco, Liliana and Tibiletti, Maria Grazia and Peterlongo, Paolo and Volorio, Sara and Manoukian, Siranoush and Pensotti, Valeria and Arnold, Norbert and Engel, Christoph and Deissler, Helmut and Gadzicki, Dorothea and Gehrig, Andrea and Kast, Karin and Rhiem, Kerstin and Meindl, Alfons and Niederacher, Dieter and Ditsch, Nina and Plendl, Hansjoerg and Preisler-Adams, Sabine and Engert, Stefanie and Sutter, Christian and Varon-Mateeva, Raymenda and Wappenschmidt, Barbara and Weber, Bernhard H. F. and Arver, Brita and Stenmark-Askmalm, Marie and Loman, Niklas and Rosenquist, Richard and Einbeigi, Zakaria and Nathanson, Katherine L. and Rebbeck, Timothy R. and Blank, Stephanie V. and Cohn, David E. and Rodriguez, Gustavo C. and Small, Laurie and Friedlander, Michael and Bae-Jump, Victoria L. and Fink-Retter, Anneliese and Rappaport, Christine and Gschwantler-Kaulich, Daphne and Pfeiler, Georg and Tea, Muy-Kheng and Lindor, Noralane M. and Kaufman, Bella and Paluch, Shani Shimon and Laitman, Yael and Skytte, Anne-Bine and Gerdes, Anne-Marie and Pedersen, Inge Sokilde and Moeller, Sanne Traasdahl and Kruse, Torben A. and Jensen, Uffe Birk and Vijai, Joseph and Sarrel, Kara and Robson, Mark and Kauff, Noah and Mulligan, Anna Marie and Glendon, Gord and Ozcelik, Hilmi and Ejlertsen, Bent and Nielsen, Finn C. and J{\o}nson, Lars and Andersen, Mette K. and Ding, Yuan Chun and Steele, Linda and Foretova, Lenka and Teul{\´e}, Alex and Lazaro, Conxi and Brunet, Joan and Pujana, Miquel Angel and Mai, Phuong L. and Loud, Jennifer T. and Walsh, Christine and Lester, Jenny and Orsulic, Sandra and Narod, Steven A. and Herzog, Josef and Sand, Sharon R. and Tognazzo, Silvia and Agata, Simona and Vaszko, Tibor and Weaver, Joellen and Stravropoulou, Alexandra V. and Buys, Saundra S. and Romero, Atocha and de la Hoya, Miguel and Aittom{\"a}ki, Kristiina and Muranen, Taru A. and Duran, Mercedes and Chung, Wendy K. and Lasa, Adriana and Dorfling, Cecilia M. and Miron, Alexander and Benitez, Javier and Senter, Leigha and Huo, Dezheng and Chan, Salina B. and Sokolenko, Anna P. and Chiquette, Jocelyne and Tihomirova, Laima and Friebel, Tara M. and Agnarsson, Bjarne A. and Lu, Karen H. and Lejbkowicz, Flavio and James, Paul A. and Hall, Per and Dunning, Alison M. and Tessier, Daniel and Cunningham, Julie and Slager, Susan L. and Chen, Wang and Hart, Steven and Stevens, Kristen and Simard, Jacques and Pastinen, Tomi and Pankratz, Vernon S. and Offit, Kenneth and Easton, Douglas F. and Chenevix-Trench, Georgia and Antoniou, Antonis C.}, title = {Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk}, series = {PLOS Genetics}, volume = {9}, journal = {PLOS Genetics}, number = {3}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1003212}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-127947}, pages = {e1003212}, year = {2013}, abstract = {BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 x 10(-8), HR = 1.14, 95\% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 x 10(-8), HR = 1.27, 95\% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 x 10(-8), HR = 1.20, 95\% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2 x 10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5\% of BRCA1 carriers at lowest risk are 28\%-50\% compared to 81\%-100\% for the 5\% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5\% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28\% or lower, whereas the 5\% at highest risk will have a risk of 63\% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.}, language = {en} } @article{BoehmVasliMaureretal.2013, author = {B{\"o}hm, Johann and Vasli, Nasim and Maurer, Marie and Cowling, Belinda and Shelton, G. Diane and Kress, Wolfram and Toussaint, Anne and Prokic, Ivana and Schara, Ulrike and Anderson, Thomas James and Weis, Joachim and Tiret, Laurent and Laporte, Jocelyn}, title = {Altered Splicing of the BIN1 Muscle-Specific Exon in Humans and Dogs with Highly Progressive Centronuclear Myopathy}, series = {PLOS Genetics}, volume = {9}, journal = {PLOS Genetics}, number = {6}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1003430}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-127590}, pages = {e1003430}, year = {2013}, abstract = {Amphiphysin 2, encoded by BIN1, is a key factor for membrane sensing and remodelling in different cell types. Homozygous BIN1 mutations in ubiquitously expressed exons are associated with autosomal recessive centronuclear myopathy (CNM), a mildly progressive muscle disorder typically showing abnormal nuclear centralization on biopsies. In addition, misregulation of BIN1 splicing partially accounts for the muscle defects in myotonic dystrophy (DM). However, the muscle-specific function of amphiphysin 2 and its pathogenicity in both muscle disorders are not well understood. In this study we identified and characterized the first mutation affecting the splicing of the muscle-specific BIN1 exon 11 in a consanguineous family with rapidly progressive and ultimately fatal centronuclear myopathy. In parallel, we discovered a mutation in the same BIN1 exon 11 acceptor splice site as the genetic cause of the canine Inherited Myopathy of Great Danes (IMGD). Analysis of RNA from patient muscle demonstrated complete skipping of exon 11 and BIN1 constructs without exon 11 were unable to promote membrane tubulation in differentiated myotubes. Comparative immunofluorescence and ultrastructural analyses of patient and canine biopsies revealed common structural defects, emphasizing the importance of amphiphysin 2 in membrane remodelling and maintenance of the skeletal muscle triad. Our data demonstrate that the alteration of the muscle-specific function of amphiphysin 2 is a common pathomechanism for centronuclear myopathy, myotonic dystrophy, and IMGD. The IMGD dog is the first faithful model for human BIN1-related CNM and represents a mammalian model available for preclinical trials of potential therapies.}, language = {en} } @article{ZahnleiterUebeEkicietal.2013, author = {Zahnleiter, Diana and Uebe, Steffen and Ekici, Arif B. and Hoyer, Juliane and Wiesener, Antje and Wieczorek, Dagmar and Kunstmann, Erdmute and Reis, Andr{\´e} and Doerr, Helmuth-Guenther and Rauch, Anita and Thiel, Christian T.}, title = {Rare Copy Number Variants Are a Common Cause of Short Stature}, series = {PLoS Genetics}, volume = {9}, journal = {PLoS Genetics}, number = {3}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1003365}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-127645}, pages = {e1003365}, year = {2013}, abstract = {Human growth has an estimated heritability of about 80\%-90\%. Nevertheless, the underlying cause of shortness of stature remains unknown in the majority of individuals. Genome-wide association studies (GWAS) showed that both common single nucleotide polymorphisms and copy number variants (CNVs) contribute to height variation under a polygenic model, although explaining only a small fraction of overall genetic variability in the general population. Under the hypothesis that severe forms of growth retardation might also be caused by major gene effects, we searched for rare CNVs in 200 families, 92 sporadic and 108 familial, with idiopathic short stature compared to 820 control individuals. Although similar in number, patients had overall significantly larger CNVs \((p-value <1 x 10^{-7})\). In a gene-based analysis of all non-polymorphic CNVs >50 kb for gene function, tissue expression, and murine knock-out phenotypes, we identified 10 duplications and 10 deletions ranging in size from 109 kb to 14 Mb, of which 7 were de novo (p < 0.03) and 13 inherited from the likewise affected parent but absent in controls. Patients with these likely disease causing 20 CNVs were smaller than the remaining group (p < 0.01). Eleven (55\%) of these CNVs either overlapped with known microaberration syndromes associated with short stature or contained GWAS loci for height. Haploinsufficiency (HI) score and further expression profiling suggested dosage sensitivity of major growth-related genes at these loci. Overall 10\% of patients carried a disease-causing CNV indicating that, like in neurodevelopmental disorders, rare CNVs are a frequent cause of severe growth retardation.}, language = {en} } @article{NeuschKuhlmannKressetal.2012, author = {Neusch, Clemens and Kuhlmann, Tanja and Kress, Wolfram and Schneider-Gold, Christiane}, title = {Late-onset myopathy of the posterior calf muscles mimicking Miyoshi myopathy unrelated to dysferlin mutation: a case report}, series = {Journal of Medical Case Reports}, volume = {6}, journal = {Journal of Medical Case Reports}, number = {345}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124365}, year = {2012}, abstract = {Introduction Miyoshi myopathy, a type of distal myopathy with predominant involvement of the posterior calf muscles, has been assigned to mutations in the dysferlin gene. However, many of the late-onset limb-girdle and distal myopathies that resemble dysferlinopathy or Miyoshi myopathy remain unclassified, even after extensive immunohistological and genetic analysis. Case presentation We report the case of a 59-year-old Caucasian man with distal myopathy and exercise-induced myalgia, preferentially of the leg muscles, closely resembling the Miyoshi phenotype. Magnetic resonance imaging of his calf muscles showed typical fatty replacement of the medial heads of the gastrocnemius muscles and soleus muscles, with progression to the adductor longus muscles over a time course of two years. However, genetic analysis revealed that the phenotype of our patient was not related to a mutation in the dysferlin gene but to a novel homozygous splice mutation in the anoctamin 5 gene. Mutations in the anoctamin 5 gene have so far been identified only in some cases of limb-girdle and distal myopathy. Mutations in the anoctamin 5 gene have been assigned to limb-girdle muscular dystrophy type 2L, while distal Miyoshi-like phenotypes have been classified as Miyoshi myopathy type 3. Conclusion The case presented in this report further strengthens the underlying genetic heterogeneity in Miyoshi myopathy-like phenotypes and adds another family to non-dysferlin, Miyoshi myopathy type 3 of late-onset. Furthermore, our case supports the recent observation that anoctamin 5 mutations are a primary cause of distal non-dysferlin myopathies. Therefore, given the increasing number of anoctamin 5 mutations in Miyoshi-like phenotypes, genetic analysis should include an anoctamin 5 screen in late-onset limb-girdle and distal myopathies.}, language = {en} } @article{RallGrimm2012, author = {Rall, Susanne and Grimm, Tiemo}, title = {Survival in Duchenne muscular dystrophy}, series = {Acta Myologica}, volume = {31}, journal = {Acta Myologica}, number = {2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124404}, pages = {117-120}, year = {2012}, abstract = {Objective: To determine the survival in a population of German patients with Duchenne muscular dystrophy. Patients and methods: Information about 94 patients born between 1970 and 1980 was obtained by telephone interviews and questionnaires. In addition to age of death or actual age during the investigation, data concerning clinical course and medical interventions were collected. Results: 67 patients with molecularly confirmed diagnoses had a median survival of 24.0 years. Patients without molecular confirmation (clinical diagnosis only) had a chance of 67 \% to reach that age. Grouping of our patient cohort according to the year of death (before and after 2000), ventilation was recognized as main intervention affecting survival with ventilated reaching a median survival of 27.0 years. For those without ventilation it was 19.0 years. Conclusion and clinical relevance: our study provides survival data for a cohort of DMD patients in Germany stratified by year of death. Median survival was 24.0 years in patients confirmed by molecular testing. Ventilated patients had a median survival of 27 years. We consider this piece of information helpful in the medical care of DMD patients.}, language = {en} } @article{GaletzkaHansmannElHajjetal.2012, author = {Galetzka, Danuta and Hansmann, Tamara and El Hajj, Nady and Weis, Eva and Irmscher, Benjamin and Ludwig, Marco and Schneider-R{\"a}tzke, Brigitte and Kohlschmidt, Nicolai and Beyer, Vera and Bartsch, Oliver and Zechner, Ulrich and Spix, Claudia and Haaf, Thomas}, title = {Monozygotic twins discordant for constitutive BRCA1 promoter methylation, childhood cancer and secondary cancer}, series = {Epigenetics}, volume = {7}, journal = {Epigenetics}, number = {1}, doi = {10.4161/epi.7.1.18814}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125386}, pages = {47-54}, year = {2012}, abstract = {We describe monozygotic twins discordant for childhood leukemia and secondary thyroid carcinoma. We used bisulfite pyrosequencing to compare the constitutive promoter methylation of BRCA1 and several other tumor suppressor genes in primary fibroblasts. The affected twin displayed an increased BRCA1 methylation (12\%), compared with her sister (3\%). Subsequent bisulfite plasmid sequencing demonstrated that 13\% (6 of 47) BRCA1 alleles were fully methylated in the affected twin, whereas her sister displayed only single CpG errors without functional implications. This between-twin methylation difference was also found in irradiated fibroblasts and untreated saliva cells. The BRCA1 epimutation may have originated by an early somatic event in the affected twin: approximately 25\% of her body cells derived from different embryonic cell lineages carry one epigenetically inactivated BRCA1 allele. This epimutation was associated with reduced basal protein levels and a higher induction of BRCA1 after DNA damage. In addition, we performed a genome-wide microarray analysis of both sisters and found several copy number variations, i.e., heterozygous deletion and reduced expression of the RSPO3 gene in the affected twin. This monozygotic twin pair represents an impressive example of epigenetic somatic mosaicism, suggesting a role for constitutive epimutations, maybe along with de novo genetic alterations in recurrent tumor development.}, language = {en} } @article{WalterReilichThieleetal.2013, author = {Walter, Maggie C. and Reilich, Peter and Thiele, Simone and Schessl, Joachim and Schreiber, Herbert and Reiners, Karlheinz and Kress, Wolfram and M{\"u}ller-Reible, Clemens and Vorgerd, Matthias and Urban, Peter and Schrank, Bertold and Deschauer, Marcus and Schlotter-Weigel, Beate and Kohnen, Ralf and Lochm{\"u}ller, Hans}, title = {Treatment of dysferlinopathy with deflazacort: a double-blind, placebo-controlled clinical trial}, series = {Orphanet Journal of Rare Diseases}, volume = {8}, journal = {Orphanet Journal of Rare Diseases}, number = {26}, issn = {1750-1172}, doi = {10.1186/1750-1172-8-26}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125663}, year = {2013}, abstract = {Background: Dysferlinopathies are autosomal recessive disorders caused by mutations in the dysferlin (DYSF) gene encoding the dysferlin protein. DYSF mutations lead to a wide range of muscular phenotypes, with the most prominent being Miyoshi myopathy (MM) and limb girdle muscular dystrophy type 2B (LGMD2B). Methods: We assessed the one-year-natural course of dysferlinopathy, and the safety and efficacy of deflazacort treatment in a double-blind, placebo-controlled cross-over trial. After one year of natural course without intervention, 25 patients with genetically defined dysferlinopathy were randomized to receive deflazacort and placebo for six months each (1 mg/kg/day in month one, 1 mg/kg every 2nd day during months two to six) in one of two treatment sequences. Results: During one year of natural course, muscle strength declined about 2\% as measured by CIDD (Clinical Investigation of Duchenne Dystrophy) score, and 76 Newton as measured by hand-held dynamometry. Deflazacort did not improve muscle strength. In contrast, there is a trend of worsening muscle strength under deflazacort treatment, which recovers after discontinuation of the study drug. During deflazacort treatment, patients showed a broad spectrum of steroid side effects. Conclusion: Deflazacort is not an effective therapy for dysferlinopathies, and off-label use is not warranted. This is an important finding, since steroid treatment should not be administered in patients with dysferlinopathy, who may be often misdiagnosed as polymyositis.}, language = {en} } @article{HansmannPliushchLeubneretal.2012, author = {Hansmann, Tamara and Pliushch, Galyna and Leubner, Monika and Kroll, Patricia and Endt, Daniela and Gehrig, Andrea and Preisler-Adams, Sabine and Wieacker, Peter and Haaf, Thomas}, title = {Constitutive promoter methylation of BRCA1 and RAD51C in patients with familial ovarian cancer and early-onset sporadic breast cancer}, series = {Human Molecular Genetics}, volume = {21}, journal = {Human Molecular Genetics}, number = {21}, doi = {10.1093/hmg/dds308}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125673}, pages = {4669-4679}, year = {2012}, abstract = {Genetic defects in breast cancer (BC) susceptibility genes, most importantly BRCA1 and BRCA2, account for ∼40\% of hereditary BC and ovarian cancer (OC). Little is known about the contribution of constitutive (soma-wide) epimutations to the remaining cases. We developed bisulfite pyrosequencing assays to screen >600 affected BRCA1/BRCA2 mutation-negative patients from the German Consortium for Hereditary Breast and Ovarian Cancer for constitutive hypermethylation of ATM, BRCA1, BRCA2, RAD51C, PTEN and TP53 in blood cells. In a second step, patients with ≥6\% promoter methylation were analyzed by bisulfite plasmid sequencing to demonstrate the presence of hypermethylated alleles (epimutations), indicative of epigenetic gene silencing. Altogether we identified nine (1.4\%) patients with constitutive BRCA1 and three (0.5\%) with RAD51C hypermethylation. Epimutations were found in both sporadic cases, in particular in 2 (5.5\%) of 37 patients with early-onset BC, and familial cases, in particular 4 (10\%) of 39 patients with OC. Hypermethylation was always confined to one of the two parental alleles in a subset (12-40\%) of the analyzed cells. Because epimutations occurred in cell types from different embryonal layers, they most likely originated in single cells during early somatic development. We propose that analogous to germline genetic mutations constitutive epimutations may serve as the first hit of tumor development. Because the role of constitutive epimutations in cancer development is likely to be largely underestimated, future strategies for effective testing of susceptibility to BC and OC should include an epimutation screen.}, language = {en} } @article{PetersenKuntzerFischeretal.2015, author = {Petersen, Jens A. and Kuntzer, Thierry and Fischer, Dirk and von der Hagen, Maja and Veronika, Angela and Lobrinus, Johannes A. and Kress, Wolfram and Rushing, Elisabeth J. and Sinnreich, Michael and Jung, Hans H.}, title = {Dysferlinopathy in Switzerland: clinical phenotypes and potential founder effects}, series = {BMC Neurology}, volume = {15}, journal = {BMC Neurology}, number = {182}, doi = {10.1186/s12883-015-0449-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-139920}, year = {2015}, abstract = {Background: Dysferlin is reduced in patients with limb girdle muscular dystrophy type 2B, Miyoshi myopathy, distal anterior compartment myopathy, and in certain Ethnic clusters. Methods: We evaluated clinical and genetic patient data from three different Swiss Neuromuscular Centers. Results: Thirteen patients from 6 non-related families were included. Age of onset was 18.8 +/- 4.3 years. In all patients, diallelic disease-causing mutations were identified in the DYSF gene. Nine patients from 3 non-related families from Central Switzerland carried the identical homozygous mutation, c.3031 + 2T>C. A possible founder effect was confirmed by haplotype analysis. Three patients from two different families carried the heterozygous mutation, c.1064_1065delAA. Two novel mutations were identified (c.2869C>T (p.Gln957Stop), c.5928G>A (p.Trp1976Stop)). Conclusions: Our study confirms the phenotypic heterogeneity associated with DYSF mutations. Two mutations (c.3031 + 2T>C, c.1064_1065delAA) appear common in Switzerland. Haplotype analysis performed on one case (c.3031 + 2T>C) suggested a possible founder effect.}, language = {en} } @article{FernandezRodriguezQuilesBlancoetal.2012, author = {Fern{\´a}ndez-Rodr{\´i}guez, Juana and Quiles, Francisco and Blanco, Ignacio and Teul{\´e}, Alex and Feliubadal{\´o}, L{\´i}dia and del Valle, Jes{\´u}s and Salinas, M{\´o}nica and Izquierdo, {\´A}ngel and Darder, Esther and Schindler, Detlev and Capell{\´a}, Gabriel and Brunet, Joan and L{\´a}zaro, Conxi and Angel Pujana, Miguel}, title = {Analysis of SLX4/FANCP in non-BRCA1/2-mutated breast cancer families}, series = {BMC Cancer}, volume = {12}, journal = {BMC Cancer}, number = {84}, doi = {10.1186/1471-2407-12-84}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-131772}, year = {2012}, abstract = {Background: Genes that, when mutated, cause Fanconi anemia or greatly increase breast cancer risk encode for proteins that converge on a homology-directed DNA damage repair process. Mutations in the SLX4 gene, which encodes for a scaffold protein involved in the repair of interstrand cross-links, have recently been identified in unclassified Fanconi anemia patients. A mutation analysis of SLX4 in German or Byelorussian familial cases of breast cancer without detected mutations in BRCA1 or BRCA2 has been completed, with globally negative results. Methods: The genomic region of SLX4, comprising all exons and exon-intron boundaries, was sequenced in 94 Spanish familial breast cancer cases that match a criterion indicating the potential presence of a highly-penetrant germline mutation, following exclusion of BRCA1 or BRCA2 mutations. Results: This mutational analysis revealed extensive genetic variation of SLX4, with 21 novel single nucleotide variants; however, none could be linked to a clear alteration of the protein function. Nonetheless, genotyping 10 variants (nine novel, all missense amino acid changes) in a set of controls (138 women and 146 men) did not detect seven of them. Conclusions: Overall, while the results of this study do not identify clearly pathogenic mutations of SLX4 contributing to breast cancer risk, further genetic analysis, combined with functional assays of the identified rare variants, may be warranted to conclusively assess the potential link with the disease.}, language = {en} } @article{SchartlWalterShenetal.2013, author = {Schartl, Manfred and Walter, Ronald B. and Shen, Yingjia and Garcia, Tzintzuni and Catchen, Julian and Amores, Angel and Braasch, Ingo and Chalopin, Domitille and Volff, Jean-Nicolas and Lesch, Klaus-Peter and Bisazza, Angelo and Minx, Pat and Hillier, LaDeana and Wilson, Richard K. and F{\"u}rstenberg, Susan and Boore, Jeffrey and Searle, Steve and Postlethwait, John H. and Warren, Wesley C.}, title = {The genome of the platyfish, Xiphophorus maculatus, provides insights into evolutionary adaptation and several complex traits}, series = {Nature Genetics}, volume = {45}, journal = {Nature Genetics}, number = {5}, doi = {10.1038/ng.2604}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-132152}, pages = {567-572}, year = {2013}, abstract = {Several attributes intuitively considered to be typical mammalian features, such as complex behavior, live birth and malignant disease such as cancer, also appeared several times independently in lower vertebrates. The genetic mechanisms underlying the evolution of these elaborate traits are poorly understood. The platyfish, X. maculatus, offers a unique model to better understand the molecular biology of such traits. We report here the sequencing of the platyfish genome. Integrating genome assembly with extensive genetic maps identified an unexpected evolutionary stability of chromosomes in fish, in contrast to in mammals. Genes associated with viviparity show signatures of positive selection, identifying new putative functional domains and rare cases of parallel evolution. We also find that genes implicated in cognition show an unexpectedly high rate of duplicate gene retention after the teleost genome duplication event, suggesting a hypothesis for the evolution of the behavioral complexity in fish, which exceeds that found in amphibians and reptiles.}, language = {en} } @article{LehnenZechnerHaaf2013, author = {Lehnen, Harald and Zechner, Urlich and Haaf, Thomas}, title = {Epigenetics of gestational diabetes mellitus and offspring health: the time for action is in early stages of life}, series = {Molecular Human Reproduction}, volume = {19}, journal = {Molecular Human Reproduction}, number = {7}, doi = {10.1093/molehr/gat020}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-132165}, pages = {415-422}, year = {2013}, abstract = {The epidemic increase of type 2 diabetes and obesity in developed countries cannot be explained by overnutrition, physical inactivity and/or genetic factors alone. Epidemiologic evidence suggests that an adverse intrauterine environment, in particular a shortage or excess of nutrients is associated with increased risks for many complex diseases later in life. An impressive example for the 'fetal origins of adult disease' is gestational diabetes mellitus which usually presents in 1\% to >10\% of third trimester pregnancies. Intrauterine hyperglycemia is not only associated with increased perinatal morbidity and mortality, but also with increased lifelong risks of the exposed offspring for obesity, metabolic, cardiovascular and malignant diseases. Accumulating evidence suggests that fetal overnutrition (and similarly undernutrition) lead to persistent epigenetic changes in developmentally important genes, influencing neuroendocrine functions, energy homeostasis and metabolism. The concept of fetal programming has important implications for reproductive medicine. Because during early development the epigenome is much more vulnerable to environmental cues than later in life, avoiding adverse environmental factors in the periconceptional and intrauterine period may be much more important for the prevention of adult disease than any (i.e. dietetic) measures in infants and adults. A successful pregnancy should not primarily be defined by the outcome at birth but also by the health status in later life.}, language = {en} } @article{AntoniouKuchenbaeckerSoucyetal.2012, author = {Antoniou, Antonis C. and Kuchenbaecker, Karoline B. and Soucy, Penny and Beesley, Jonathan and Chen, Xiaoqing and McGuffog, Lesley and Lee, Andrew and Barrowdale, Daniel and Healey, Sue and Sinilnikova, Olga M. and Caligo, Maria A. and Loman, Niklas and Harbst, Katja and Lindblom, Annika and Arver, Brita and Rosenquist, Richard and Karlsson, Per and Nathanson, Kate and Domchek, Susan and Rebbeck, Tim and Jakubowska, Anna and Lubinski, Jan and Jaworska, Katarzyna and Durda, Katarzyna and Zlowowcka-Perłowska, Elżbieta and Osorio, Ana and Dur{\´a}n, Mercedes and Andr{\´e}s, Raquel and Ben{\´i}tez, Javier and Hamann, Ute and Hogervorst, Frans B. and van Os, Theo A. and Verhoef, Senno and Meijers-Heijboer, Hanne E. J. and Wijnen, Juul and Garcia, Encarna B. G{\´o}mez and Ligtenberg, Marjolijn J. and Kriege, Mieke and Coll{\´e}e, Margriet and Ausems, Margreet G. E. M. and Oosterwijk, Jan C. and Peock, Susan and Frost, Debra and Ellis, Steve D. and Platte, Radka and Fineberg, Elena and Evans, D. Gareth and Lalloo, Fiona and Jacobs, Chris and Eeles, Ros and Adlard, Julian and Davidson, Rosemarie and Cole, Trevor and Cook, Jackie and Paterson, Joan and Douglas, Fiona and Brewer, Carole and Hodgson, Shirley and Morrison, Patrick J. and Walker, Lisa and Rogers, Mark T. and Donaldson, Alan and Dorkins, Huw and Godwin, Andrew K. and Bove, Betsy and Stoppa-Lyonnet, Dominique and Houdayer, Claude and Buecher, Bruno and de Pauw, Antoine and Mazoyer, Sylvie and Calender, Alain and L{\´e}on{\´e}, M{\´e}lanie and Bressac-de Paillerets, Brigitte and Caron, Olivier and Sobol, Hagay and Frenay, Marc and Prieur, Fabienne and Ferrer, Sandra Fert and Mortemousque, Isabelle and Buys, Saundra and Daly, Mary and Miron, Alexander and Terry, Mary Beth and Hopper, John L. and John, Esther M. and Southey, Melissa and Goldgar, David and Singer, Christian F. and Fink-Retter, Anneliese and Muy-Kheng, Tea and Geschwantler Kaulich, Daphne and Hansen, Thomas V. O. and Nielsen, Finn C. and Barkardottir, Rosa B. and Gaudet, Mia and Kirchhoff, Tomas and Joseph, Vijai and Dutra-Clarke, Ana and Offit, Kenneth and Piedmonte, Marion and Kirk, Judy and Cohn, David and Hurteau, Jean and Byron, John and Fiorica, James and Toland, Amanda E. and Montagna, Marco and Oliani, Cristina and Imyanitov, Evgeny and Isaacs, Claudine and Tihomirova, Laima and Blanco, Ignacio and Lazaro, Conxi and Teul{\´e}, Alex and Del Valle, J. and Gayther, Simon A. and Odunsi, Kunle and Gross, Jenny and Karlan, Beth Y. and Olah, Edith and Teo, Soo-Hwang and Ganz, Patricia A. and Beattie, Mary S. and Dorfling, Cecelia M. and Jansen van Rensburg, Elizabeth and Diez, Orland and Kwong, Ava and Schmutzler, Rita K. and Wappenschmidt, Barbara and Engel, Christoph and Meindl, Alfons and Ditsch, Nina and Arnold, Norbert and Heidemann, Simone and Niederacher, Dieter and Preisler-Adams, Sabine and Gadzicki, Dorothea and Varon-Mateeva, Raymonda and Deissler, Helmut and Gehrig, Andrea and Sutter, Christian and Kast, Karin and Fiebig, Britta and Sch{\"a}fer, Dieter and Caldes, Trinidad and de la Hoya, Miguel and Nevanlinna, Heli and Muranen, Taru A. and Lesp{\´e}rance, Bernard and Spurdle, Amanda B. and Neuhausen, Susan L. and Ding, Yuan C. and Wang, Xianshu and Fredericksen, Zachary and Pankratz, Vernon S. and Lindor, Noralane M. and Peterlongo, Paulo and Manoukian, Siranoush and Peissel, Bernard and Zaffaroni, Daniela and Bonanni, Bernardo and Bernard, Loris and Dolcetti, Riccardo and Papi, Laura and Ottini, Laura and Radice, Paolo and Greene, Mark H. and Loud, Jennifer T. and Andrulis, Irene L. and Ozcelik, Hilmi and Mulligan, Anna Marie and Glendon, Gord and Thomassen, Mads and Gerdes, Anne-Marie and Jensen, Uffe B. and Skytte, Anne-Bine and Kruse, Torben A. and Chenevix-Trench, Georgia and Couch, Fergus J. and Simard, Jacques and Easton, Douglas F.}, title = {Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers}, series = {Breast Cancer Research}, volume = {14}, journal = {Breast Cancer Research}, number = {R33}, organization = {CIMBA; SWE-BRCA; HEBON; EMBRACE; GEMO Study Collaborators; kConFab Investigators}, doi = {10.1186/bcr3121}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130449}, year = {2012}, abstract = {Introduction: Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 (ZNF365), rs704010 (ZMIZ1), rs2380205 (10p15), rs614367 (11q13), rs1292011 (12q24), rs10771399 (12p11 near PTHLH) and rs865686 (9q31.2). Methods: To evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12,599 BRCA1 and 7,132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework. Results: Only SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele hazard ratio (HR) = 0.87, 95\% CI: 0.81 to 0.94, P-trend = 3 x 10\(^{-4}\)). The association was restricted to mutations proven or predicted to lead to absence of protein expression (HR = 0.82, 95\% CI: 0.74 to 0.90, P-trend = 3.1 x 10\(^{-5}\), P-difference = 0.03). Four SNPs were associated with the risk of breast cancer for BRCA2 mutation carriers: rs10995190, P-trend = 0.015; rs1011970, P-trend = 0.048; rs865686, 2df P = 0.007; rs1292011 2df P = 0.03. rs10771399 (PTHLH) was predominantly associated with estrogen receptor (ER)-negative breast cancer for BRCA1 mutation carriers (HR = 0.81, 95\% CI: 0.74 to 0.90, P-trend = 4 x 10\(^{-5}\)) and there was marginal evidence of association with ER- negative breast cancer for BRCA2 mutation carriers (HR = 0.78, 95\% CI: 0.62 to 1.00, P-trend = 0.049). Conclusions: The present findings, in combination with previously identified modifiers of risk, will ultimately lead to more accurate risk prediction and an improved understanding of the disease etiology in BRCA1 and BRCA2 mutation carriers.}, language = {en} } @article{SemmlerSacconiBachetal.2014, author = {Semmler, Anna-Lena and Sacconi, Sabrina and Bach, J. Elisa and Liebe, Claus and B{\"u}rmann, Jan and Kley, Rudolf A. and Ferbert, Andreas and Anderheiden, Roland and Van den Bergh, Peter and Martin, Jean-Jacques and De Jonghe, Peter and Neuen-Jacob, Eva and M{\"u}ller, Oliver and Deschauer, Marcus and Bergmann, Markus and Schr{\"o}der, J. Michael and Vorgerd, Matthias and Schulz, J{\"o}rg B. and Weis, Joachim and Kress, Wolfram and Claeys, Kristl G.}, title = {Unusual multisystemic involvement and a novel BAG3 mutation revealed by NGS screening in a large cohort of myofibrillar myopathies}, series = {Orphanet Journal of Rare Diseases}, volume = {9}, journal = {Orphanet Journal of Rare Diseases}, number = {121}, issn = {1750-1172}, doi = {10.1186/s13023-014-0121-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-115623}, year = {2014}, abstract = {Background: Myofibrillar myopathies (MFM) are a group of phenotypically and genetically heterogeneous neuromuscular disorders, which are characterized by protein aggregations in muscle fibres and can be associated with multisystemic involvement. Methods: We screened a large cohort of 38 index patients with MFM for mutations in the nine thus far known causative genes using Sanger and next generation sequencing (NGS). We studied the clinical and histopathological characteristics in 38 index patients and five additional relatives (n = 43) and particularly focused on the associated multisystemic symptoms. Results: We identified 14 heterozygous mutations (diagnostic yield of 37\%), among them the novel p. Pro209Gln mutation in the BAG3 gene, which was associated with onset in adulthood, a mild phenotype and an axonal sensorimotor polyneuropathy, in the absence of giant axons at the nerve biopsy. We revealed several novel clinical phenotypes and unusual multisystemic presentations with previously described mutations: hearing impairment with a FLNC mutation, dysphonia with a mutation in DES and the first patient with a FLNC mutation presenting respiratory insufficiency as the initial symptom. Moreover, we described for the first time respiratory insufficiency occurring in a patient with the p. Gly154Ser mutation in CRYAB. Interestingly, we detected a polyneuropathy in 28\% of the MFM patients, including a BAG3 and a MYOT case, and hearing impairment in 13\%, including one patient with a FLNC mutation and two with mutations in the DES gene. In four index patients with a mutation in one of the MFM genes, typical histological findings were only identified at the ultrastructural level (29\%). Conclusions: We conclude that extraskeletal symptoms frequently occur in MFM, particularly cardiac and respiratory involvement, polyneuropathy and/or deafness. BAG3 mutations should be considered even in cases with a mild phenotype or an adult onset. We identified a genetic defect in one of the known genes in less than half of the MFM patients, indicating that more causative genes are still to be found. Next generation sequencing techniques should be helpful in achieving this aim.}, language = {en} } @article{TayebiJamsheerFloettmannetal.2014, author = {Tayebi, Naeimeh and Jamsheer, Aleksander and Fl{\"o}ttmann, Ricarda and Sowinska-Seidler, Anna and Doelken, Sandra C. and Oehl-Jaschkowitz, Barbara and H{\"u}lsemann, Wiebke and Habenicht, Rolf and Klopocki, Eva and Mundlos, Sefan and Spielmann, Malte}, title = {Deletions of exons with regulatory activity at the DYNC1I1 locus are associated with split-hand/split-foot malformation: array CGH screening of 134 unrelated families}, series = {Orphanet Journal of Rare Diseases}, volume = {9}, journal = {Orphanet Journal of Rare Diseases}, number = {108}, issn = {1750-1172}, doi = {10.1186/s13023-014-0108-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-115759}, year = {2014}, abstract = {Background: A growing number of non-coding regulatory mutations are being identified in congenital disease. Very recently also some exons of protein coding genes have been identified to act as tissue specific enhancer elements and were therefore termed exonic enhancers or "eExons". Methods: We screened a cohort of 134 unrelated families with split-hand/split-foot malformation (SHFM) with high resolution array CGH for CNVs with regulatory potential. Results: In three families with an autosomal dominant non-syndromic SHFM phenotype we detected microdeletions encompassing the exonic enhancer (eExons) 15 and 17 of DYNC1I1. In a fourth family, who had hearing loss in addition to SHFM, we found a larger deletion of 510 kb including the eExons of DYNC1I1 and, in addition, the human brain enhancer hs1642. Exons 15 and 17 of DYNC1I1 are known to act as tissue specific limb enhancers of DLX5/6, two genes that have been shown to be associated with SHFM in mice. In our cohort of 134 unrelated families with SHFM, deletions of the eExons of DYNC1I1 account for approximately 3\% of the cases, while 17p13.3 duplications were identified in 13\% of the families, 10q24 duplications in 12\%, and TP63 mutations were detected in 4\%. Conclusions: We reduce the minimal critical region for SHFM1 to 78 kb. Hearing loss, however, appears to be associated with deletions of a more telomeric region encompassing the brain enhancer element hs1642. Thus, SHFM1 as well as hearing loss at the same locus are caused by deletion of regulatory elements. Deletions of the exons with regulatory potential of DYNC1I1 are an example of the emerging role of exonic enhancer elements and their implications in congenital malformation syndromes.}, language = {en} } @article{OsorioMilneKuchenbaeckeretal.2014, author = {Osorio, Ana and Milne, Roger L. and Kuchenbaecker, Karoline and Vaclov{\´a}, Tereza and Pita, Guillermo and Alonso, Rosario and Peterlongo, Paolo and Blanco, Ignacio and de la Hoya, Miguel and Duran, Mercedes and Diez, Orland and Ram{\´o}n y Cajal, Teresa and Konstantopoulou, Irene and Mart{\´i}nez-Bouzas, Christina and Conejero, Raquel Andr{\´e}s and Soucy, Penny and McGuffog, Lesley and Barrowdale, Daniel and Lee, Andrew and Arver, Brita and Rantala, Johanna and Loman, Niklas and Ehrencrona, Hans and Olopade, Olufunmilayo I. and Beattie, Mary S. and Domchek, Susan M. and Nathanson, Katherine and Rebbeck, Timothy R. and Arun, Banu K. and Karlan, Beth Y. and Walsh, Christine and Lester, Jenny and John, Esther M. and Whittemore, Alice S. and Daly, Mary B. and Southey, Melissa and Hopper, John and Terry, Mary B. and Buys, Saundra S. and Janavicius, Ramunas and Dorfling, Cecilia M. and van Rensburg, Elizabeth J. and Steele, Linda and Neuhausen, Susan L. and Ding, Yuan Chun and Hansen, Thomas V. O. and J{\o}nson, Lars and Ejlertsen, Bent and Gerdes, Anne-Marie and Infante, Mar and Herr{\´a}ez, Bel{\´e}n and Moreno, Leticia Thais and Weitzel, Jeffrey N. and Herzog, Josef and Weeman, Kisa and Manoukian, Siranoush and Peissel, Bernard and Zaffaroni, Daniela and Scuvera, Guilietta and Bonanni, Bernardo and Mariette, Frederique and Volorio, Sara and Viel, Alessandra and Varesco, Liliana and Papi, Laura and Ottini, Laura and Tibiletti, Maria Grazia and Radice, Paolo and Yannoukakos, Drakoulis and Garber, Judy and Ellis, Steve and Frost, Debra and Platte, Radka and Fineberg, Elena and Evans, Gareth and Lalloo, Fiona and Izatt, Louise and Eeles, Ros and Adlard, Julian and Davidson, Rosemarie and Cole, Trevor and Eccles, Diana and Cook, Jackie and Hodgson, Shirley and Brewer, Carole and Tischkowitz, Marc and Douglas, Fiona and Porteous, Mary and Side, Lucy and Walker, Lisa and Morrison, Patrick and Donaldson, Alan and Kennedy, John and Foo, Claire and Godwin, Andrew K. and Schmutzler, Rita Katharina and Wappenschmidt, Barbara and Rhiem, Kerstin and Engel, Christoph and Meindl, Alftons and Ditsch, Nina and Arnold, Norbert and Plendl, Hans J{\"o}rg and Niederacher, Dieter and Sutter, Christian and Wang-Gohrke, Shan and Steinemann, Doris and Preisler-Adams, Sabine and Kast, Karin and Varon-Mateeva, Raymonda and Gehrig, Andrea and Stoppa-Lyonnet, Dominique and Sinilnikova, Olga M. and Mazoyer, Sylvie and Damiola, Francesca and Poppe, Bruce and Claes, Kathleen and Piedmonte, Marion and Tucker, Kathy and Backes, Floor and Rodr{\´i}guez, Gustavo and Brewster, Wendy and Wakeley, Katie and Rutherford, Thomas and Cald{\´e}s, Trinidad and Nevanlinna, Heli and Aittom{\"a}ki, Kristiina and Rookus, Matti A. and van Os, Theo A. M. and van der Kolk, Lizet and de Lange, J. L. and Meijers-Heijboer, Hanne E. J. and van der Hout, A. H. and van Asperen, Christi J. and Gom{\´e}z Garcia, Encarna B. and Encarna, B. and Hoogerbrugge, Nicoline and Coll{\´e}e, J. Margriet and van Deurzen, Carolien H. M. and van der Luijt, Rob B. and Devilee, Peter and Olah, Edith and L{\´a}zaro, Conxi and Teul{\´e}, Alex and Men{\´e}ndez, Mireia and Jakubowska, Anna and Cybulski, Cezary and Gronwald, Jecek and Lubinski, Jan and Durda, Katarzyna and Jaworska-Bieniek, Katarzyna and Johannsson, Oskar Th. and Maugard, Christine and Montagna, Marco and Tognazzo, Silvia and Teixeira, Manuel R. and Healey, Sue and Olswold, Curtis and Guidugli, Lucia and Lindor, Noralane and Slager, Susan and Szabo, Csilla I. and Vijai, Joseph and Robson, Mark and Kauff, Noah and Zhang, Liying and Rau-Murthy, Rohini and Fink-Retter, Anneliese and Singer, Christine F. and Rappaport, Christine and Kaulich, Daphne Geschwantler and Pfeiler, Georg and Tea, Muy-Kheng and Berger, Andreas and Phelan, Catherine M. and Greene, Mark H. and Mai, Phuong L. and Lejbkowicz, Flavio and Andrulis, Irene and Mulligan, Anna Marie and Glendon, Gord and Toland, Amanda Ewart and Bojesen, Anders and Pedersen, Inge Sokilde and Sunde, Lone and Thomassen, Mads and Kruse, Torben A. and Jensen, Uffe Birk and Friedman, Eitan and Laitman, Yeal and Shimon, Shanie Paluch and Simard, Jaques and Easton, Douglas F. and Offit, Kenneth and Couch, Fergus J. and Chenevix-Trench, Georgia and Antoniou, Antonis C. and Benitez, Javier}, title = {DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers}, series = {PLOS Genetics}, volume = {4}, journal = {PLOS Genetics}, number = {e1004256}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1004256}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-116820}, year = {2014}, abstract = {Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p<0.05 in the combined analysis. Four of the five genes for which strongest evidence of association was observed were DNA glycosylases. The strongest evidence was for rs1466785 in the NEIL2 (endonuclease VIII-like 2) gene (HR: 1.09, 95\% CI (1.03-1.16), p = 2.7x10(-3)) for association with breast cancer risk in BRCA2 mutation carriers, and rs2304277 in the OGG1 (8-guanine DNA glycosylase) gene, with ovarian cancer risk in BRCA1 mutation carriers (HR: 1.12 95\% CI: 1.03-1.21, p = 4.8x10(-3)). DNA glycosylases involved in the first steps of the BER pathway may be associated with cancer risk in BRCA1/2 mutation carriers and should be more comprehensively studied.}, language = {en} } @article{KohlhaseBogdanovaSchuermannetal.2014, author = {Kohlhase, Sandra and Bogdanova, Natalia V. and Sch{\"u}rmann, Peter and Bermisheva, Marina and Khusnutdinova, Elza and Antonenkova, Natalia and Park-Simon, Tjoung-Won and Hillemanns, Peter and Meyer, Andreas and Christiansen, Hans and Schindler, Detlev and D{\"o}rk, Thilo}, title = {Mutation Analysis of the ERCC4/FANCQ Gene in Hereditary Breast Cancer}, series = {PLOS ONE}, volume = {9}, journal = {PLOS ONE}, number = {1}, doi = {10.1371/journal.pone.0085334}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-117582}, pages = {e85334}, year = {2014}, abstract = {The ERCC4 protein forms a structure-specific endonuclease involved in the DNA damage response. Different cancer syndromes such as a subtype of Xeroderma pigmentosum, XPF, and recently a subtype of Fanconi Anemia, FA-Q, have been attributed to biallelic ERCC4 gene mutations. To investigate whether monoallelic ERCC4 gene defects play some role in the inherited component of breast cancer susceptibility, we sequenced the whole ERCC4 coding region and flanking untranslated portions in a series of 101 Byelorussian and German breast cancer patients selected for familial disease (set 1, n = 63) or for the presence of the rs1800067 risk haplotype (set 2, n = 38). This study confirmed six known and one novel exonic variants, including four missense substitutions but no truncating mutation. Missense substitution p.R415Q (rs1800067), a previously postulated breast cancer susceptibility allele, was subsequently screened for in a total of 3,698 breast cancer cases and 2,868 controls from Germany, Belarus or Russia. The Gln415 allele appeared protective against breast cancer in the German series, with the strongest effect for ductal histology (OR 0.67; 95\%CI 0.49; 0.92; p = 0.003), but this association was not confirmed in the other two series, with the combined analysis yielding an overall Mantel-Haenszel OR of 0.94 (95\% CI 0.81; 1.08). There was no significant effect of p.R415Q on breast cancer survival in the German patient series. The other three detected ERCC4 missense mutations included two known rare variants as well as a novel substitution, p.E17V, that we identified on a p.R415Q haplotype background. The p.E17V mutation is predicted to be probably damaging but was present in just one heterozygous patient. We conclude that the contribution of ERCC4/FANCQ coding mutations to hereditary breast cancer in Central and Eastern Europe is likely to be small.}, language = {en} } @article{vonBernuthRavindranDuetal.2014, author = {von Bernuth, Horst and Ravindran, Ethiraj and Du, Hang and Froehler, Sebastian and Strehl, Karoline and Kraemer, Nadine and Issa-Jahns, Lina and Amulic, Borko and Ninnemann, Olaf and Xiao, Mei-Sheng and Eirich, Katharina and Koelsch, Uwe and Hauptmann, Kathrin and John, Rainer and Schindler, Detlev and Wahn, Volker and Chen, Wei and Kaindl, Angela M.}, title = {Combined immunodeficiency develops with age in Immunodeficiency-centromeric instability-facial anomalies syndrome 2 (ICF2)}, series = {Orphanet Journal of Rare Dieeases}, volume = {9}, journal = {Orphanet Journal of Rare Dieeases}, doi = {10.1186/s13023-014-0116-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-114859}, pages = {116}, year = {2014}, abstract = {The autosomal recessive immunodeficiency-centromeric instability-facial anomalies syndrome (ICF) is characterized by immunodeficiency, developmental delay, and facial anomalies. ICF2, caused by biallelic ZBTB24 gene mutations, is acknowledged primarily as an isolated B-cell defect. Here, we extend the phenotype spectrum by describing, in particular, for the first time the development of a combined immune defect throughout the disease course as well as putative autoimmune phenomena such as granulomatous hepatitis and nephritis. We also demonstrate impaired cell-proliferation and increased cell death of immune and non-immune cells as well as data suggesting a chromosome separation defect in addition to the known chromosome condensation defect.}, language = {en} }