@article{VonaMazaheriLinetal.2021, author = {Vona, Barbara and Mazaheri, Neda and Lin, Sheng-Jia and Dunbar, Lucy A. and Maroofian, Reza and Azaiez, Hela and Booth, Kevin T. and Vitry, Sandrine and Rad, Aboulfazl and R{\"u}schendorf, Franz and Varshney, Pratishtha and Fowler, Ben and Beetz, Christian and Alagramam, Kumar N. and Murphy, David and Shariati, Gholamreza and Sedaghat, Alireza and Houlden, Henry and Petree, Cassidy and VijayKumar, Shruthi and Smith, Richard J. H. and Haaf, Thomas and El-Amraoui, Aziz and Bowl, Michael R. and Varshney, Gaurav K. and Galehdari, Hamid}, title = {A biallelic variant in CLRN2 causes non-syndromic hearing loss in humans}, series = {Human Genetics}, volume = {140}, journal = {Human Genetics}, number = {6}, issn = {1432-1203}, doi = {10.1007/s00439-020-02254-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-267740}, pages = {915-931}, year = {2021}, abstract = {Deafness, the most frequent sensory deficit in humans, is extremely heterogeneous with hundreds of genes involved. Clinical and genetic analyses of an extended consanguineous family with pre-lingual, moderate-to-profound autosomal recessive sensorineural hearing loss, allowed us to identify CLRN2, encoding a tetraspan protein, as a new deafness gene. Homozygosity mapping followed by exome sequencing identified a 14.96 Mb locus on chromosome 4p15.32p15.1 containing a likely pathogenic missense variant in CLRN2 (c.494C > A, NM_001079827.2) segregating with the disease. Using in vitro RNA splicing analysis, we show that the CLRN2 c.494C > A variant leads to two events: (1) the substitution of a highly conserved threonine (uncharged amino acid) to lysine (charged amino acid) at position 165, p.(Thr165Lys), and (2) aberrant splicing, with the retention of intron 2 resulting in a stop codon after 26 additional amino acids, p.(Gly146Lysfs*26). Expression studies and phenotyping of newly produced zebrafish and mouse models deficient for clarin 2 further confirm that clarin 2, expressed in the inner ear hair cells, is essential for normal organization and maintenance of the auditory hair bundles, and for hearing function. Together, our findings identify CLRN2 as a new deafness gene, which will impact future diagnosis and treatment for deaf patients.}, language = {en} } @article{KittelSchneiderDavidovaKaloketal.2022, author = {Kittel-Schneider, Sarah and Davidova, Petra and Kalok, Miriam and Essel, Corina and Ahmed, Fadia Ben and Kingeter, Yasmina and Matentzoglu, Maria and Leutritz, Anna and Kersken, Katharina and Koreny, Carolin and Weber, Heike and Kollert, Leoniee and McNeill, Rihannon V. and Reif, Andreas and Bahlmann, Franz and Trautmann-Villalba, Patricia}, title = {A pilot study of multilevel analysis of BDNF in paternal and maternal perinatal depression}, series = {Archives of Women's Mental Health}, volume = {25}, journal = {Archives of Women's Mental Health}, number = {1}, issn = {1435-1102}, doi = {10.1007/s00737-021-01197-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-268849}, pages = {237-249}, year = {2022}, abstract = {Depression in the perinatal period is common in mothers worldwide. Emerging research indicates that fathers are also at risk of developing perinatal depression. However, knowledge regarding biological risk factors and pathophysiological mechanisms of perinatal depression is still scarce, particularly in fathers. It has been suggested that the neurotrophin BDNF may play a role in maternal perinatal depression; however, there is currently no data regarding paternal perinatal depression. For this pilot study, 81 expecting parents were recruited and assessed at several time points. We screened for depression using EPDS and MADRS, investigated several psychosocial variables, and took blood samples for BDNF val66met genotyping, epigenetic, and protein analysis. Between pregnancy and 12 months postpartum (pp), we found that 3.7 to 15.7\% of fathers screened positive for depression, and 9.6 to 24\% of mothers, with at least a twofold increased prevalence in both parents using MADRS compared with EPDS. We also identified several psychosocial factors associated with perinatal depression in both parents. The data revealed a trend that lower BDNF levels correlated with maternal depressive symptoms at 3 months pp. In the fathers, no significant correlations between BDNF and perinatal depression were found. Pregnant women demonstrated lower BDNF methylation and BDNF protein expression compared with men; however, these were found to increase postpartum. Lastly, we identified correlations between depressive symptoms and psychosocial/neurobiological factors. The data suggest that BDNF may play a role in maternal perinatal depression, but not paternal.}, 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{vanDintherZhangWeidaueretal.2013, author = {van Dinther, Maarten and Zhang, Juan and Weidauer, Stella E. and Boschert, Verena and Muth, Eva-Maria and Knappik, Achim and de Gorter, David J. J. and van Kasteren, Puck B. and Frisch, Christian and M{\"u}ller, Thomas D. and ten Dijke, Peter}, title = {Anti-Sclerostin Antibody Inhibits Internalization of Sclerostin and Sclerostin-Mediated Antagonism of Wnt/LRP6 Signaling}, series = {PLoS ONE}, volume = {8}, journal = {PLoS ONE}, number = {4}, doi = {10.1371/journal.pone.0062295}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130981}, pages = {e62295}, year = {2013}, abstract = {Sclerosteosis is a rare high bone mass disease that is caused by inactivating mutations in the SOST gene. Its gene product, Sclerostin, is a key negative regulator of bone formation and might therefore serve as a target for the anabolic treatment of osteoporosis. The exact molecular mechanism by which Sclerostin exerts its antagonistic effects on Wnt signaling in bone forming osteoblasts remains unclear. Here we show that Wnt3a-induced transcriptional responses and induction of alkaline phosphatase activity, an early marker of osteoblast differentiation, require the Wnt co-receptors LRP5 and LRP6. Unlike Dickkopf1 (DKK1), Sclerostin does not inhibit Wnt-3a-induced phosphorylation of LRP5 at serine 1503 or LRP6 at serine 1490. Affinity labeling of cell surface proteins with \([^{125} I]\) Sclerostin identified LRP6 as the main specific Sclerostin receptor in multiple mesenchymal cell lines. When cells were challenged with Sclerostin fused to recombinant green fluorescent protein (GFP) this was internalized, likely via a Clathrin-dependent process, and subsequently degraded in a temperature and proteasome-dependent manner. Ectopic expression of LRP6 greatly enhanced binding and cellular uptake of Sclerostin-GFP, which was reduced by the addition of an excess of non-GFP-fused Sclerostin. Finally, an anti-Sclerostin antibody inhibited the internalization of Sclerostin-GFP and binding of Sclerostin to LRP6. Moreover, this antibody attenuated the antagonistic activity of Sclerostin on canonical Wnt-induced responses.}, language = {en} } @article{MitchellMacarthurGanetal.2014, author = {Mitchell, Anna L. and Macarthur, Katie D. R. and Gan, Earn H. and Baggott, Lucy E. and Wolff, Anette S. B. and Skinningsrud, Beate and Platt, Hazel and Short, Andrea and Lobell, Anna and Kampe, Olle and Bensing, Sophie and Betterle, Corrado and Kasperlik-Zaluska, Anna and Zurawek, Magdalena and Fichna, Marta and Kockum, Ingrid and Eriksson, Gabriel Nordling and Ekwall, Olov and Wahlberg, Jeanette and Dahlqvist, Per and Hulting, Anna-Lena and Penna-Martinez, Marissa and Meyer, Gesine and Kahles, Heinrich and Badenhoop, Klaus and Hahner, Stephanie and Quinkler, Marcus and Falorni, Alberto and Phipps-Green, Amanda and Merriman, Tony R. and Ollier, William and Cordell, Heather J. and Undlien, Dag and Czarnocka, Barbara and Husebye, Eystein and Pearce, Simon H. S.}, title = {Association of Autoimmune Addison's Disease with Alleles of STAT4 and GATA3 in European Cohorts}, series = {PLOS ONE}, volume = {9}, journal = {PLOS ONE}, number = {3}, doi = {10.1371/journal.pone.0088991}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-117105}, pages = {e88991}, year = {2014}, abstract = {Background: Gene variants known to contribute to Autoimmune Addison's disease (AAD) susceptibility include those at the MHC, MICA, CIITA, CTLA4, PTPN22, CYP27B1, NLRP-1 and CD274 loci. The majority of the genetic component to disease susceptibility has yet to be accounted for. Aim: To investigate the role of 19 candidate genes in AAD susceptibility in six European case-control cohorts. Methods: A sequential association study design was employed with genotyping using Sequenom iPlex technology. In phase one, 85 SNPs in 19 genes were genotyped in UK and Norwegian AAD cohorts (691 AAD, 715 controls). In phase two, 21 SNPs in 11 genes were genotyped in German, Swedish, Italian and Polish cohorts (1264 AAD, 1221 controls). In phase three, to explore association of GATA3 polymorphisms with AAD and to determine if this association extended to other autoimmune conditions, 15 SNPs in GATA3 were studied in UK and Norwegian AAD cohorts, 1195 type 1 diabetes patients from Norway, 650 rheumatoid arthritis patients from New Zealand and in 283 UK Graves' disease patients. Meta-analysis was used to compare genotype frequencies between the participating centres, allowing for heterogeneity. Results: We report significant association with alleles of two STAT4 markers in AAD cohorts (rs4274624: P = 0.00016; rs10931481: P = 0.0007). In addition, nominal association of AAD with alleles at GATA3 was found in 3 patient cohorts and supported by meta-analysis. Association of AAD with CYP27B1 alleles was also confirmed, which replicates previous published data. Finally, nominal association was found at SNPs in both the NF-kappa B1 and IL23A genes in the UK and Italian cohorts respectively. Conclusions: Variants in the STAT4 gene, previously associated with other autoimmune conditions, confer susceptibility to AAD. Additionally, we report association of GATA3 variants with AAD: this adds to the recent report of association of GATA3 variants with rheumatoid arthritis.}, language = {en} } @phdthesis{Bartke2018, author = {Bartke, Lena}, title = {Assoziationsstudien zur Untersuchung der Bedeutung verschiedener Polymorphismen der serotonergen Gene FEV und TPH2 f{\"u}r affektive St{\"o}rungen und adultes ADHS}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-166952}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2018}, abstract = {Das serotonerge System bildet schon seit Jahrzehnten einen Schwerpunkt in der psychiatrischen Grundlagenforschung. Seinen weit verzweigten Leitungsbahnen wird eine global-modulatorische Eigenschaft f{\"u}r die Aufrechterhaltung des Gleichgewichts zwischen unterschiedlichen Hirnregionen und unterschiedlichen Neurotransmitter-systemen zugeschrieben (H{\"u}ther und R{\"u}ther, 2000). Dar{\"u}ber hinaus ist die serotonerge Neurotransmission ein Hauptmodulator emotionalen Verhaltens, das Angst und {\"A}ngstlichkeit ebenso umfasst wie Aggression und Impulsivit{\"a}t (Lesch et al., 2003). In der vorliegenden Arbeit wurden im Sinne eines Kandidatengenansatzes zwei Assoziationsstudien durchgef{\"u}hrt. Im ersten Teil wurde versucht, eine m{\"o}gliche Assoziation zwischen der Erkrankung an affektiven St{\"o}rungen und drei vorbeschriebenen SNPs des FEV-Gens aufzudecken. FEV ist das humane Homolog des in mehreren Tierversuchen untersuchten Pet-1-Gens, dem vor allem eine zentrale Bedeutung in der embryonalen Entwicklung des serotonergen Systems zugeschrieben wird. Zus{\"a}tzlich wurde ein 286 bp langer Abschnitt des Exon 3 sequenziert, um die H{\"a}ufigkeit der sieben in diesem Abschnitt beschriebenen SNPs bei unipolar depressiven Patienten abzusch{\"a}tzen und ggf. neue Varianten zu detektieren. Der zweite Teil untersuchte das Auftreten zweier bereits von anderen Autoren beschriebener SNPs des TPH2-Gen bei an der adulten Form des ADHS leidenden Patienten im Vergleich zu einer Kontrollgruppe. Die im zentralen serotonergen System dominierende Tryptophanhydroxylase 2 (TPH2) ist das erste, geschwindigkeitsbegrenzende Enzym der Serotonin-Biosynthese. Die Genotypisierung der einzelnen SNPs erfolgte mit unterschiedlichen Methoden. So kam sowohl die PCR, der Restriktionsenzymverdau, die Minisequenzierung (SNaPshot®) als auch die MALDI-ToF Massenspektrometrie und die Sequenzierung zum Einsatz, die Auftrennung einzelner Schnittprodukte erfolgte durch die Gelelektrophorese. Die erste Stichprobe umfasste 270 Patienten (davon 179 weiblich) mittleren Alters mit einer Diagnose aus dem affektiven Formenkreis (180 mit bipolar-affektiver St{\"o}rung gem{\"a}ß den DSM-IV Kriterien, weitere 90 Patienten mit einer rezidivierenden unipolaren depressiven St{\"o}rung) sowie 362 (davon 174 weibliche) Kontrollpersonen. Die Stichproben der zweiten Studie umfassten 284 am adulten ADHS (Diagnose nach DSM IV) leidende Patienten (140 davon weiblich) und 120 Kontrollpersonen (61 davon weiblich). Statistisch wurden die Daten sowohl auf Einzelmarker- als auch auf Haplotypniveau ausgewertet. In beiden Studien konnte keine Assoziation der untersuchten Polymorphismen des FEV- bzw. TPH2-Gens mit der jeweiligen Erkrankung (affektive St{\"o}rung / adultes ADHS), weder auf Einzelmarker- noch auf Haplotypniveau, nachgewiesen werden. Die Sequenzierung des 286 bp langen Abschnitts von Exon 3 des FEV-Gens zeigt eine ausgepr{\"a}gte Konservierung der Sequenz dieses Gens, wie sie auch von anderen Autoren beschrieben wurde. Die hier untersuchten Kandidatengene FEV und TPH2 sind auch weiterhin interessante Ansatzpunkte f{\"u}r die psychiatrische Grundlagenforschung. Die Aufkl{\"a}rung der genauen Wirkungsweise von FEV und seine Rolle in der Entwicklung des menschlichen serotonergen Systems erscheint jedoch vordergr{\"u}ndig, um zun{\"a}chst Funktion, Interaktionen und m{\"o}gliche pathogenetische Mechanismen aufzudecken und dann gezielter die Einfl{\"u}sse bestimmter Polymorphismen zu untersuchen.}, subject = {Serotonin}, language = {de} } @article{GaiserGeissingerSchattenbergetal.2012, author = {Gaiser, Timo and Geissinger, Eva and Schattenberg, Torsten and Scharf, Hanns-Peter and D{\"u}rken, Matthias and Dinter, Dietmar and Rosenwald, Andreas and Marx, Alexander}, title = {Case report: a unique pediatric case of a primary CD8 expressing ALK-1 positive anaplastic large cell lymphoma of skeletal muscle}, series = {Diagnostic Pathology}, volume = {7}, journal = {Diagnostic Pathology}, number = {38}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-135381}, year = {2012}, abstract = {Primary involvement of skeletal muscle is a very rare event in ALK-1 positive anaplastic large cell lymphoma (ALCL). We describe a case of a 10-year old boy presenting with a three week history of pain and a palpable firm swelling at the dorsal aspect of the left thigh. Histological examination of the lesion revealed a tumoral and diffuse polymorphic infiltration of the muscle by large lymphoid cells. Tumor cells displayed eccentric, lobulated "horse shoe" or "kidney-shape" nuclei. The cells showed immunohistochemical positivity for CD30, ALK-1, CD2, CD3, CD7, CD8, and Perforin. Fluorescence in situ hybridization analysis revealed a characteristic rearrangement of the ALK-1 gene in 2p23 leading to the diagnosis of ALK-1 positive ALCL. Chemotherapy according to the ALCL-99-NHL-BFM protocol was initiated and resulted in a complete remission after two cycles. This case illustrates the unusual presentation of a pediatric ALCL in soft tissue with a good response to chemotherapy.}, language = {en} } @article{GabelliniHarnischMcCarthyetal.1985, author = {Gabellini, N. and Harnisch, U. and McCarthy, J. E. and Hauska, G. and Sebald, Walter}, title = {Cloning and expression of the fbc operon encoding the FeS protein, cytochrome b and cytochrome c\(_1\) from the Rhodopseudomonas sphaeroides b/c\(_1\) complex}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-62642}, year = {1985}, abstract = {The gene for the FeS protein of the Rhodopseudomonas sphaeroides b/c1 complex was identified by means of crosshybridization with a segment of the gene encoding the corresponding FeS protein of Neurospora crassa. Plasmids (pRSF1-14) containing the cross-hybridizing region, covering in total 13.5 kb of chromosomal DNA, were expressed in vitro in a homologous system. One RSF plasmid directed the synthesis of all three main polypeptides of the R. sphaeroides blc1 complex: the FeS protein, cytochrome b and cytochrome c1• The FeS protein and cytochrome c1 were apparently synthesized as precursor fonns. None of the pRSF plasmids directed the synthesis of the 10-kd polypeptide found in b/c1 complex preparations. Partial sequencing of the cloned region was performed. Several sites of strong homology between R. sphaeroides and eukaryotic polypeptides of the b/c1 complex were identified. The genes encode the three b/c1 polypeptides in the order: (5') FeS protein, cytochrome b, cytochrome c1• The three genes are transcribed to give a polycistronic mRNA of 2.9 kb. This transcriptional unit has been designated the jbc operon; its coding capacity corresponds to the size of the polycistronic mRNA assuming that only the genes for the FeS protein (jbcF), cytochrome b (jbcß) and cytochrome c1 (jbcC) are present. This could indicate that these three subunits constitute the minimal catalytic unit of the b/c1 complex from photosynthetic membranes.}, subject = {Biochemie}, language = {en} } @article{FaganDollarLuetal.2014, author = {Fagan, Jeremy K. and Dollar, Gretchen and Lu, Qiuheng and Barnett, Austen and Jorge, Joaquin Pechuan and Schlosser, Andreas and Pfleger, Cathie and Adler, Paul and Jenny, Andreas}, title = {Combover/CG10732, a Novel PCP Effector for Drosophila Wing Hair Formation}, series = {PLOS ONE}, volume = {9}, journal = {PLOS ONE}, number = {9}, issn = {1932-6203}, doi = {10.1371/journal.pone.0107311}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-115394}, pages = {e107311}, year = {2014}, abstract = {The polarization of cells is essential for the proper functioning of most organs. Planar Cell Polarity (PCP), the polarization within the plane of an epithelium, is perpendicular to apical-basal polarity and established by the non-canonical Wnt/Fz-PCP signaling pathway. Within each tissue, downstream PCP effectors link the signal to tissue specific readouts such as stereocilia orientation in the inner ear and hair follicle orientation in vertebrates or the polarization of ommatidia and wing hairs in Drosophila melanogaster. Specific PCP effectors in the wing such as Multiple wing hairs (Mwh) and Rho Kinase (Rok) are required to position the hair at the correct position and to prevent ectopic actin hairs. In a genome-wide screen in vitro, we identified Combover (Cmb)/CG10732 as a novel Rho kinase substrate. Overexpression of Cmb causes the formation of a multiple hair cell phenotype (MHC), similar to loss of rok and mwh. This MHC phenotype is dominantly enhanced by removal of rok or of other members of the PCP effector gene family. Furthermore, we show that Cmb physically interacts with Mwh, and cmb null mutants suppress the MHC phenotype of mwh alleles. Our data indicate that Cmb is a novel PCP effector that promotes to wing hair formation, a function that is antagonized by Mwh.}, language = {en} } @article{VandeKerkhofFeenstravanderHeijdenetal.2012, author = {Van de Kerkhof, Noortje W. A. and Feenstra, Ilse and van der Heijden, Frank M. M. A. and de Leeuw, Nicole and Pfundt, Rolph and St{\"o}ber, Gerald and Egger, Jos I. M. and Verhoeven, Willem M. A.}, title = {Copy number variants in a sample of patients with psychotic disorders: is standard screening relevant for actual clinical practice?}, series = {Neuropsychiatric Disease and Treatment}, volume = {8}, journal = {Neuropsychiatric Disease and Treatment}, doi = {10.2147/NDT.S32903}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-134769}, pages = {295-300}, year = {2012}, abstract = {With the introduction of new genetic techniques such as genome-wide array comparative genomic hybridization, studies on the putative genetic etiology of schizophrenia have focused on the detection of copy number variants (CNVs), ie, microdeletions and/or microduplications, that are estimated to be present in up to 3\% of patients with schizophrenia. In this study, out of a sample of 100 patients with psychotic disorders, 80 were investigated by array for the presence of CNVs. The assessment of the severity of psychiatric symptoms was performed using standardized instruments and ICD-10 was applied for diagnostic classification. In three patients, a submicroscopic CNV was demonstrated, one with a loss in 1q21.1 and two with a gain in 1p13.3 and 7q11.2, respectively. The association between these or other CNVs and schizophrenia or schizophrenia-like psychoses and their clinical implications still remain equivocal. While the CNV affected genes may enhance the vulnerability for psychiatric disorders via effects on neuronal architecture, these insights have not resulted in major changes in clinical practice as yet. Therefore, genome-wide array analysis should presently be restricted to those patients in whom psychotic symptoms are paired with other signs, particularly dysmorphisms and intellectual impairment.}, language = {en} }