TY - JOUR A1 - Rickman, Kimberly A. A1 - Lach, Francis P. A1 - Abhyankar, Avinash A1 - Donovan, Frank X. A1 - Sanborn, Erica M. A1 - Kennedy, Jennifer A. A1 - Sougnez, Carrie A1 - Gabriel, Stacey B. A1 - Elemento, Olivier A1 - Chandrasekharappa, Settara C. A1 - Schindler, Detlev A1 - Auerbach, Arleen D. A1 - Smogorzewska, Agata T1 - Deficiency of UBE2T, the E2 Ubiquitin Ligase Necessary for FANCD2 and FANCI Ubiquitination, Causes FA-T Subtype of Fanconi Anemia JF - Cell Reports N2 - Fanconi anemia (FA) is a rare bone marrow failure and cancer predisposition syndrome resulting from pathogenic mutations in genes encoding proteins participating in the repair of DNA interstrand crosslinks (ICLs). Mutations in 17 genes (FANCA-FANCS) have been identified in FA patients, defining 17 complementation groups. Here, we describe an individual presenting with typical FA features who is deficient for the ubiquitin-conjugating enzyme (E2), UBE2T. UBE2T is known to interact with FANCL, the E3 ubiquitin-ligase component of the multiprotein FA core complex, and is necessary for the monoubiquitination of FANCD2 and FANCI. Proband fibroblasts do not display FANCD2 and FANCI monoubiquitination, do not form FANCD2 foci following treatment with mitomycin C, and are hypersensitive to crosslinking agents. These cellular defects are complemented by expression of wild-type UBE2T, demonstrating that deficiency of the protein UBE2T can lead to Fanconi anemia. UBE2T gene gains an alias of FANCT. KW - cross-link repair KW - DNA repair KW - gene KW - mutations KW - aldehydes KW - somatic mosaicism KW - pathway KW - monoubiquitination KW - diagnosis KW - proteins Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-151525 VL - 12 SP - 35 EP - 41 ER - TY - JOUR A1 - Urban, Lara A1 - Remmele, Christian W. A1 - Dittrich, Marcus A1 - Schwarz, Roland F. A1 - Müller, Tobias T1 - covRNA: discovering covariate associations in large-scale gene expression data JF - BMC Reserach Notes N2 - Objective The biological interpretation of gene expression measurements is a challenging task. While ordination methods are routinely used to identify clusters of samples or co-expressed genes, these methods do not take sample or gene annotations into account. We aim to provide a tool that allows users of all backgrounds to assess and visualize the intrinsic correlation structure of complex annotated gene expression data and discover the covariates that jointly affect expression patterns. Results The Bioconductor package covRNA provides a convenient and fast interface for testing and visualizing complex relationships between sample and gene covariates mediated by gene expression data in an entirely unsupervised setting. The relationships between sample and gene covariates are tested by statistical permutation tests and visualized by ordination. The methods are inspired by the fourthcorner and RLQ analyses used in ecological research for the analysis of species abundance data, that we modified to make them suitable for the distributional characteristics of both, RNA-Seq read counts and microarray intensities, and to provide a high-performance parallelized implementation for the analysis of large-scale gene expression data on multi-core computational systems. CovRNA provides additional modules for unsupervised gene filtering and plotting functions to ensure a smooth and coherent analysis workflow. KW - Multivariate analysis KW - Fourthcorner analysis KW - RLQ analysis KW - Transcriptomics KW - High-throughput data KW - Visualization KW - Ordination methods KW - RNA-Seq analysis KW - Microarray analysis Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229258 VL - 13 ER - TY - JOUR A1 - Vona, Barbara A1 - Hofrichter, Michaela A. H. A1 - Schröder, Jörg A1 - Shehata-Dieler, Wafaa A1 - Nanda, Indrajit A1 - Haaf, Thomas T1 - Hereditary hearing loss SNP-microarray pilot study JF - BMC Research Notes N2 - Objectives: Despite recent advancements in diagnostic tools, the genomic landscape of hereditary hearing loss remains largely uncharacterized. One strategy to understand genome-wide aberrations includes the analysis of copy number variation that can be mapped using SNP-microarray technology. A growing collection of literature has begun to uncover the importance of copy number variation in hereditary hearing loss. This pilot study underpins a larger effort that involves the stage-wise analysis of hearing loss patients, many of whom have advanced to high-throughput sequencing analysis. Data description: Our data originate from the Infinium HumanOmni1-Quad v1.0 SNP-microarrays (Illumina) that provide useful markers for genome-wide association studies and copy number variation analysis. This dataset comprises a cohort of 108 individuals (99 with hearing loss, 9 normal hearing family members) for the purpose of understanding the genetic contribution of copy number variations to hereditary hearing loss. These anonymized SNP-microarray data have been uploaded to the NCBI Gene Expression Omnibus and are intended to benefit other investigators interested in aggregating platform-matched array patient datasets or as part of a supporting reference tool for other laboratories to better understand recurring copy number variations in other genetic disorders. KW - copy number variation KW - genotyping arrays KW - hereditary hearing loss KW - illumina KW - infinium HumanOmni1-Quad KW - SNP-microarray Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-176239 VL - 11 IS - 391 ER - TY - JOUR A1 - Ziegler, Georg C. A1 - Radtke, Franziska A1 - Vitale, Maria Rosaria A1 - Preuße, André A1 - Klopocki, Eva A1 - Herms, Stefan A1 - Lesch, Klaus-Peter T1 - Generation of multiple human iPSC lines from peripheral blood mononuclear cells of two SLC2A3 deletion and two SLC2A3 duplication carriers JF - Stem Cell Research N2 - Copy number variants of SLC2A3, which encodes the glucose transporter GLUT3, are associated with several neuropsychiatric and cardiac diseases. Here, we report the successful reprogramming of peripheral blood mononuclear cells from two SLC2A3 duplication and two SLC2A3 deletion carriers and subsequent generation of two transgene-free iPSC clones per donor by Sendai viral transduction. All eight clones represent bona fide hiPSCs with high expression of pluripotency genes, ability to differentiate into cells of all three germ layers and normal karyotype. The generated cell lines will be helpful to enlighten the role of glucometabolic alterations in pathophysiological processes shared across organ boundaries. KW - congenital heart-deffects KW - transporter gene SLC2A3 KW - copy-number variation Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-264696 VL - 56 ER - TY - JOUR A1 - Prelog, Martina A1 - Hilligardt, Deborah A1 - Schmidt, Christian A. A1 - Przybylski, Grzegorz K. A1 - Leierer, Johannes A1 - Almanzar, Giovanni A1 - El Hajj, Nady A1 - Lesch, Klaus-Peter A1 - Arolt, Volker A1 - Zwanzger, Peter A1 - Haaf, Thomas A1 - Domschke, Katharina T1 - Hypermethylation of FOXP3 Promoter and Premature Aging of the Immune System in Female Patients with Panic Disorder? JF - PLoS ONE N2 - Immunological abnormalities associated with pathological conditions, such as higher infection rates, inflammatory diseases, cancer or cardiovascular events are common in patients with panic disorder. In the present study, T cell receptor excision circles (TRECs), Forkhead-Box-Protein P3 gene (FOXP3) methylation of regulatory T cells (Tregs) and relative telomere lengths (RTLs) were investigated in a total and subsamples of 131 patients with panic disorder as compared to 131 age- and sex-matched healthy controls in order to test for a potential dysfunction and premature aging of the immune system in anxiety disorders. Significantly lower TRECs (p = 0.004) as well as significant hypermethylation of the FOXP3 promoter region (p = 0.005) were observed in female (but not in male) patients with panic disorder as compared to healthy controls. No difference in relative telomere length was discerned between patients and controls, but significantly shorter telomeres in females, smokers and older persons within the patient group. The presently observed reduced TRECs in panic disorder patients and FOXP3 hypermethylation in female patients with panic disorder potentially reflect impaired thymus and immunosuppressive Treg function, which might partly account for the known increased morbidity and mortality of anxiety disorders conferred by e.g. cancer and cardiovascular disorders. KW - DNA methylation KW - antidepressants KW - regulatory T cells KW - panic disorder KW - treatment guidelines KW - telomere length KW - inflammatory diseases KW - anxiety disorders Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-179684 VL - 11 IS - 6 ER - TY - JOUR A1 - Bauer, Benedikt A1 - Mally, Angela A1 - Liedtke, Daniel T1 - Zebrafish embryos and larvae as alternative animal models for toxicity testing JF - International Journal of Molecular Sciences N2 - Prerequisite to any biological laboratory assay employing living animals is consideration about its necessity, feasibility, ethics and the potential harm caused during an experiment. The imperative of these thoughts has led to the formulation of the 3R-principle, which today is a pivotal scientific standard of animal experimentation worldwide. The rising amount of laboratory investigations utilizing living animals throughout the last decades, either for regulatory concerns or for basic science, demands the development of alternative methods in accordance with 3R to help reduce experiments in mammals. This demand has resulted in investigation of additional vertebrate species displaying favourable biological properties. One prominent species among these is the zebrafish (Danio rerio), as these small laboratory ray-finned fish are well established in science today and feature outstanding biological characteristics. In this review, we highlight the advantages and general prerequisites of zebrafish embryos and larvae before free-feeding stages for toxicological testing, with a particular focus on cardio-, neuro, hepato- and nephrotoxicity. Furthermore, we discuss toxicokinetics, current advances in utilizing zebrafish for organ toxicity testing and highlight how advanced laboratory methods (such as automation, advanced imaging and genetic techniques) can refine future toxicological studies in this species. KW - danio rerio KW - alternative methods KW - organ toxicity KW - 3R KW - transgenic animals Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284225 SN - 1422-0067 VL - 22 IS - 24 ER - TY - JOUR A1 - Doll, Julia A1 - Vona, Barbara A1 - Schnapp, Linda A1 - Rüschendorf, Franz A1 - Khan, Imran A1 - Khan, Saadullah A1 - Muhammad, Noor A1 - Alam Khan, Sher A1 - Nawaz, Hamed A1 - Khan, Ajmal A1 - Ahmad, Naseer A1 - Kolb, Susanne M. A1 - Kühlewein, Laura A1 - Labonne, Jonathan D. J. A1 - Layman, Lawrence C. A1 - Hofrichter, Michaela A. H. A1 - Röder, Tabea A1 - Dittrich, Marcus A1 - Müller, Tobias A1 - Graves, Tyler D. A1 - Kong, Il-Keun A1 - Nanda, Indrajit A1 - Kim, Hyung-Goo A1 - Haaf, Thomas T1 - Genetic Spectrum of Syndromic and Non-Syndromic Hearing Loss in Pakistani Families JF - Genes N2 - The current molecular genetic diagnostic rates for hereditary hearing loss (HL) vary considerably according to the population background. Pakistan and other countries with high rates of consanguineous marriages have served as a unique resource for studying rare and novel forms of recessive HL. A combined exome sequencing, bioinformatics analysis, and gene mapping approach for 21 consanguineous Pakistani families revealed 13 pathogenic or likely pathogenic variants in the genes GJB2, MYO7A, FGF3, CDC14A, SLITRK6, CDH23, and MYO15A, with an overall resolve rate of 61.9%. GJB2 and MYO7A were the most frequently involved genes in this cohort. All the identified variants were either homozygous or compound heterozygous, with two of them not previously described in the literature (15.4%). Overall, seven missense variants (53.8%), three nonsense variants (23.1%), two frameshift variants (15.4%), and one splice-site variant (7.7%) were observed. Syndromic HL was identified in five (23.8%) of the 21 families studied. This study reflects the extreme genetic heterogeneity observed in HL and expands the spectrum of variants in deafness-associated genes. KW - genetic diagnosis KW - consanguinity KW - genome-wide linkage analysis KW - hearing loss KW - Pakistan KW - exome sequencing Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-219293 SN - 2073-4425 VL - 11 IS - 11 ER - TY - JOUR A1 - Dumont, Martine A1 - Weber-Lassalle, Nana A1 - Joly-Beauparlant, Charles A1 - Ernst, Corinna A1 - Droit, Arnaud A1 - Feng, Bing-Jian A1 - Dubois, Stéphane A1 - Collin-Deschesnes, Annie-Claude A1 - Soucy, Penny A1 - Vallée, Maxime A1 - Fournier, Frédéric A1 - Lemaçon, Audrey A1 - Adank, Muriel A. A1 - Allen, Jamie A1 - Altmüller, Janine A1 - Arnold, Norbert A1 - Ausems, Margreet G. E. M. A1 - Berutti, Riccardo A1 - Bolla, Manjeet K. A1 - Bull, Shelley A1 - Carvalho, Sara A1 - Cornelissen, Sten A1 - Dufault, Michael R. A1 - Dunning, Alison M. A1 - Engel, Christoph A1 - Gehrig, Andrea A1 - Geurts-Giele, Willemina R. R. A1 - Gieger, Christian A1 - Green, Jessica A1 - Hackmann, Karl A1 - Helmy, Mohamed A1 - Hentschel, Julia A1 - Hogervorst, Frans B. L. A1 - Hollestelle, Antoinette A1 - Hooning, Maartje J. A1 - Horváth, Judit A1 - Ikram, M. Arfan A1 - Kaulfuß, Silke A1 - Keeman, Renske A1 - Kuang, Da A1 - Luccarini, Craig A1 - Maier, Wolfgang A1 - Martens, John W. M. A1 - Niederacher, Dieter A1 - Nürnberg, Peter A1 - Ott, Claus-Eric A1 - Peters, Annette A1 - Pharoah, Paul D. P. A1 - Ramirez, Alfredo A1 - Ramser, Juliane A1 - Riedel-Heller, Steffi A1 - Schmidt, Gunnar A1 - Shah, Mitul A1 - Scherer, Martin A1 - Stäbler, Antje A1 - Strom, Tim M. A1 - Sutter, Christian A1 - Thiele, Holger A1 - van Asperen, Christi J. A1 - van der Kolk, Lizet A1 - van der Luijt, Rob B. A1 - Volk, Alexander E. A1 - Wagner, Michael A1 - Waisfisz, Quinten A1 - Wang, Qin A1 - Wang-Gohrke, Shan A1 - Weber, Bernhard H. F. A1 - Devilee, Peter A1 - Tavtigian, Sean A1 - Bader, Gary D. A1 - Meindl, Alfons A1 - Goldgar, David E. A1 - Andrulis, Irene L. A1 - Schmutzler, Rita K. A1 - Easton, Douglas F. A1 - Schmidt, Marjanka K. A1 - Hahnen, Eric A1 - Simard, Jacques T1 - Uncovering the contribution of moderate-penetrance susceptibility genes to breast cancer by whole-exome sequencing and targeted enrichment sequencing of candidate genes in women of European ancestry JF - Cancers N2 - Rare variants in at least 10 genes, including BRCA1, BRCA2, PALB2, ATM, and CHEK2, are associated with increased risk of breast cancer; however, these variants, in combination with common variants identified through genome-wide association studies, explain only a fraction of the familial aggregation of the disease. To identify further susceptibility genes, we performed a two-stage whole-exome sequencing study. In the discovery stage, samples from 1528 breast cancer cases enriched for breast cancer susceptibility and 3733 geographically matched unaffected controls were sequenced. Using five different filtering and gene prioritization strategies, 198 genes were selected for further validation. These genes, and a panel of 32 known or suspected breast cancer susceptibility genes, were assessed in a validation set of 6211 cases and 6019 controls for their association with risk of breast cancer overall, and by estrogen receptor (ER) disease subtypes, using gene burden tests applied to loss-of-function and rare missense variants. Twenty genes showed nominal evidence of association (p-value < 0.05) with either overall or subtype-specific breast cancer. Our study had the statistical power to detect susceptibility genes with effect sizes similar to ATM, CHEK2, and PALB2, however, it was underpowered to identify genes in which susceptibility variants are rarer or confer smaller effect sizes. Larger sample sizes would be required in order to identify such genes. KW - breast cancer KW - genetic susceptibility KW - whole-exome sequencing KW - moderate-penetrance genes Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-281768 SN - 2072-6694 VL - 14 IS - 14 ER - TY - JOUR A1 - Engel, Christoph A1 - Rhiem, Kerstin A1 - Hahnen, Eric A1 - Loibl, Sibylle A1 - Weber, Karsten E. A1 - Seiler, Sabine A1 - Zachariae, Silke A1 - Hauke, Jan A1 - Wappenschmidt, Barbara A1 - Waha, Anke A1 - Blümcke, Britta A1 - Kiechle, Marion A1 - Meindl, Alfons A1 - Niederacher, Dieter A1 - Bartram, Claus R. A1 - Speiser, Dorothee A1 - Schlegelberger, Brigitte A1 - Arnold, Norbert A1 - Wieacker, Peter A1 - Leinert, Elena A1 - Gehrig, Andrea A1 - Briest, Susanne A1 - Kast, Karin A1 - Riess, Olaf A1 - Emons, Günter A1 - Weber, Bernhard H. F. A1 - Engel, Jutta A1 - Schmutzler, Rita K. T1 - Prevalence of pathogenic BRCA1/2 germline mutations among 802 women with unilateral triple-negative breast cancer without family cancer history JF - BMC Cancer N2 - Background There is no international consensus up to which age women with a diagnosis of triple-negative breast cancer (TNBC) and no family history of breast or ovarian cancer should be offered genetic testing for germline BRCA1 and BRCA2 (gBRCA) mutations. Here, we explored the association of age at TNBC diagnosis with the prevalence of pathogenic gBRCA mutations in this patient group. Methods The study comprised 802 women (median age 40 years, range 19-76) with oestrogen receptor, progesterone receptor, and human epidermal growth factor receptor type 2 negative breast cancers, who had no relatives with breast or ovarian cancer. All women were tested for pathogenic gBRCA mutations. Logistic regression analysis was used to explore the association between age at TNBC diagnosis and the presence of a pathogenic gBRCA mutation. Results A total of 127 women with TNBC(15.8%) were gBRCA mutation carriers (BRCA1: n = 118, 14.7%; BRCA2: n = 9, 1. 1%). The mutation prevalence was 32.9% in the age group 20-29 years compared to 6.9% in the age group 60-69 years. Logistic regression analysis revealed a significant increase of mutation frequency with decreasing age at diagnosis (odds ratio 1.87 per 10 year decrease, 95% CI 1.50-2.32, p < 0.001). gBRCA mutation risk was predicted to be > 10% for women diagnosed below approximately 50 years. Conclusions Based on the general understanding that a heterozygous mutation probability of 10% or greater justifies gBRCA mutation screening, women with TNBC diagnosed before the age of 50 years and no familial history of breast and ovarian cancer should be tested for gBRCA mutations. In Germany, this would concern approximately 880 women with newly diagnosed TNBC per year, of whom approximately 150 are expected to be identified as carriers of a pathogenic gBRCA mutation. KW - hereditary breast and ovarian cancer KW - BRCA1 KW - BRCA2 KW - triple-negative breast cancer Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226763 VL - 18 ER - TY - JOUR A1 - Sathyanarayana, Vijaya A1 - Lee, Beth A1 - Wright, Neville B. A1 - Santos, Rui A1 - Bonney, Denise A1 - Wynn, Robert A1 - Patel, Leena A1 - Chandler, Kate A1 - Cheesman, Ed A1 - Schindler, Detlev A1 - Webb, Nicholas J. A. A1 - Meyer, Stefan T1 - Patterns and frequency of renal abnormalities in Fanconi anaemia: implications for long-term management JF - Pediatric Nephrology N2 - Fanconi anaemia (FA) is an inherited disease with bone marrow failure, variable congenital and developmental abnormalities, and cancer predisposition. With improved survival, non-haematological manifestations of FA become increasingly important for long-term management. While renal abnormalities are recognized, detailed data on patterns and frequency and implications for long-term management are sparse. We reviewed clinical course and imaging findings of FA patients with respect to renal complications in our centre over a 25-year period to formulate some practical suggestions for guidelines for management of renal problems associated with FA. Thirty patients including four sibling sets were reviewed. On imaging, 14 had evidence of anatomical abnormalities of the kidneys. Two cases with severe phenotype, including renal abnormalities, had chronic kidney disease (CKD) at diagnosis. Haematopoietic stem cell transplantation was complicated by significant acute kidney injury (AKI) in three cases. In three patients, there was CKD at long-term follow-up. All patients had normal blood pressure. Evaluation of renal anatomy with ultrasound imaging is important at diagnostic workup of FA. While CKD is uncommon at diagnosis, our data suggests that the incidence of CKD increases with age, in particular after haematopoietic stem cell transplantation. Monitoring of renal function is essential for management of FA. Based on these long-term clinical observations, we formulate some practical guidelines for assessment and management of renal abnormalities in FA. KW - Fanconi anaemia KW - Renal abnormalities KW - Long-term follow-up Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227400 VL - 33 IS - 9 ER - TY - JOUR A1 - Weber-Lassalle, Nana A1 - Hauke, Jan A1 - Ramser, Juliane A1 - Richters, Lisa A1 - Groß, Eva A1 - Blümcke, Britta A1 - Gehrig, Andrea A1 - Kahlert, Anne-Karin A1 - Müller, Clemens R. A1 - Hackmann, Karl A1 - Honisch, Ellen A1 - Weber-Lassalle, Konstantin A1 - Niederacher, Dieter A1 - Borde, Julika A1 - Thiele, Holger A1 - Ernst, Corinna A1 - Altmüller, Janine A1 - Neidhardt, Guido A1 - Nürnberg, Peter A1 - Klaschik, Kristina A1 - Schroeder, Christopher A1 - Platzer, Konrad A1 - Volk, Alexander E. A1 - Wang-Gohrke, Shan A1 - Just, Walter A1 - Auber, Bernd A1 - Kubisch, Christian A1 - Schmidt, Gunnar A1 - Horvath, Judit A1 - Wappenschmidt, Barbara A1 - Engel, Christoph A1 - Arnold, Norbert A1 - Dworniczak, Bernd A1 - Rhiem, Kerstin A1 - Meindl, Alfons A1 - Schmutzler, Rita K. A1 - Hahnen, Eric T1 - BRIP1 loss-of-function mutations confer high risk for familial ovarian cancer, but not familial breast cancer JF - Breast Cancer Research N2 - Background Germline mutations in the BRIP1 gene have been described as conferring a moderate risk for ovarian cancer (OC), while the role of BRIP1 in breast cancer (BC) pathogenesis remains controversial. Methods To assess the role of deleterious BRIP1 germline mutations in BC/OC predisposition, 6341 well-characterized index patients with BC, 706 index patients with OC, and 2189 geographically matched female controls were screened for loss-of-function (LoF) mutations and potentially damaging missense variants. All index patients met the inclusion criteria of the German Consortium for Hereditary Breast and Ovarian Cancer for germline testing and tested negative for pathogenic BRCA1/2 variants. Results BRIP1 LoF mutations confer a high OC risk in familial index patients (odds ratio (OR) = 20.97, 95% confidence interval (CI) = 12.02–36.57, P < 0.0001) and in the subgroup of index patients with late-onset OC (OR = 29.91, 95% CI = 14.99–59.66, P < 0.0001). No significant association of BRIP1 LoF mutations with familial BC was observed (OR = 1.81 95% CI = 1.00–3.30, P = 0.0623). In the subgroup of familial BC index patients without a family history of OC there was also no apparent association (OR = 1.42, 95% CI = 0.70–2.90, P = 0.3030). In 1027 familial BC index patients with a family history of OC, the BRIP1 mutation prevalence was significantly higher than that observed in controls (OR = 3.59, 95% CI = 1.43–9.01; P = 0.0168). Based on the negative association between BRIP1 LoF mutations and familial BC in the absence of an OC family history, we conclude that the elevated mutation prevalence in the latter cohort was driven by the occurrence of OC in these families. Compared with controls, predicted damaging rare missense variants were significantly more prevalent in OC (P = 0.0014) but not in BC (P = 0.0693) patients. Conclusions To avoid ambiguous results, studies aimed at assessing the impact of candidate predisposition gene mutations on BC risk might differentiate between BC index patients with an OC family history and those without. In familial cases, we suggest that BRIP1 is a high-risk gene for late-onset OC but not a BC predisposition gene, though minor effects cannot be excluded. KW - breast cancer KW - ovarian cancer KW - BRIP1 gene KW - germline mutations Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233433 VL - 20 ER - TY - JOUR A1 - Pluta, Natalie A1 - Hoffjan, Sabine A1 - Zimmer, Frederic A1 - Köhler, Cornelia A1 - Lücke, Thomas A1 - Mohr, Jennifer A1 - Vorgerd, Matthias A1 - Nguyen, Hoa Huu Phuc A1 - Atlan, David A1 - Wolf, Beat A1 - Zaum, Ann-Kathrin A1 - Rost, Simone T1 - Homozygous inversion on chromosome 13 involving SGCG detected by short read whole genome sequencing in a patient suffering from limb-girdle muscular dystrophy JF - Genes N2 - New techniques in molecular genetic diagnostics now allow for accurate diagnosis in a large proportion of patients with muscular diseases. Nevertheless, many patients remain unsolved, although the clinical history and/or the muscle biopsy give a clear indication of the involved genes. In many cases, there is a strong suspicion that the cause must lie in unexplored gene areas, such as deep-intronic or other non-coding regions. In order to find these changes, next-generation sequencing (NGS) methods are constantly evolving, making it possible to sequence entire genomes to reveal these previously uninvestigated regions. Here, we present a young woman who was strongly suspected of having a so far genetically unsolved sarcoglycanopathy based on her clinical history and muscle biopsy. Using short read whole genome sequencing (WGS), a homozygous inversion on chromosome 13 involving SGCG and LINC00621 was detected. The breakpoint in intron 2 of SGCG led to the absence of γ-sarcoglycan, resulting in the manifestation of autosomal recessive limb-girdle muscular dystrophy 5 (LGMDR5) in the young woman. KW - inversion KW - sarcoglycanopathy KW - whole genome sequencing (WGS) KW - next generation sequencing (NGS) KW - LGMDR5 KW - muscle disease KW - genetic diagnostics Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288122 SN - 2073-4425 VL - 13 IS - 10 ER - TY - JOUR A1 - Nanda, Indrajit A1 - Schröder, Sarah K. A1 - Steinlein, Claus A1 - Haaf, Thomas A1 - Buhl, Eva M. A1 - Grimm, Domink G. A1 - Weiskirchen, Ralf T1 - Rat hepatic stellate cell line CFSC-2G: genetic markers and short tandem repeat profile useful for cell line authentication JF - Cells N2 - Hepatic stellate cells (HSCs) are also known as lipocytes, fat-storing cells, perisinusoidal cells, or Ito cells. These liver-specific mesenchymal cells represent about 5% to 8% of all liver cells, playing a key role in maintaining the microenvironment of the hepatic sinusoid. Upon chronic liver injury or in primary culture, these cells become activated and transdifferentiate into a contractile phenotype, i.e., the myofibroblast, capable of producing and secreting large quantities of extracellular matrix compounds. Based on their central role in the initiation and progression of chronic liver diseases, cultured HSCs are valuable in vitro tools to study molecular and cellular aspects of liver diseases. However, the isolation of these cells requires special equipment, trained personnel, and in some cases needs approval from respective authorities. To overcome these limitations, several immortalized HSC lines were established. One of these cell lines is CFSC, which was originally established from cirrhotic rat livers induced by carbon tetrachloride. First introduced in 1991, this cell line and derivatives thereof (i.e., CFSC-2G, CFSC-3H, CFSC-5H, and CFSC-8B) are now used in many laboratories as an established in vitro HSC model. We here describe molecular features that are suitable for cell authentication. Importantly, chromosome banding and multicolor spectral karyotyping (SKY) analysis demonstrate that the CFSC-2G genome has accumulated extensive chromosome rearrangements and most chromosomes exist in multiple copies producing a pseudo-triploid karyotype. Furthermore, our study documents a defined short tandem repeat (STR) profile including 31 species-specific markers, and a list of genes expressed in CFSC-2G established by bulk mRNA next-generation sequencing (NGS). KW - liver KW - extracellular matrix KW - hepatic stellate cell KW - myofibroblast KW - fibrosis KW - stress fibers KW - spectral karyotyping KW - rhodamine–phalloidin stain KW - next-generation sequencing KW - STR profile Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288067 SN - 2073-4409 VL - 11 IS - 18 ER - TY - JOUR A1 - Ferreira, Manuel A. A1 - Gamazon, Eric R. A1 - Al-Ejeh, Fares A1 - Aittomäki, Kristiina A1 - Andrulis, Irene L. A1 - Anton-Culver, Hoda A1 - Arason, Adalgeir A1 - Arndt, Volker A1 - Aronson, Kristan J. A1 - Arun, Banu K. A1 - Asseryanis, Ella A1 - Azzollini, Jacopo A1 - Balmaña, Judith A1 - Barnes, Daniel R. A1 - Barrowdale, Daniel A1 - Beckmann, Matthias W. A1 - Behrens, Sabine A1 - Benitez, Javier A1 - Bermisheva, Marina A1 - Bialkowska, Katarzyna A1 - Blomqvist, Carl A1 - Bogdanova, Natalia V. A1 - Bojesen, Stig E. A1 - Bolla, Manjeet K. A1 - Borg, Ake A1 - Brauch, Hiltrud A1 - Brenner, Hermann A1 - Broeks, Annegien A1 - Burwinkel, Barbara A1 - Caldés, Trinidad A1 - Caligo, Maria A. A1 - Campa, Daniele A1 - Campbell, Ian A1 - Canzian, Federico A1 - Carter, Jonathan A1 - Carter, Brian D. A1 - Castelao, Jose E. A1 - Chang-Claude, Jenny A1 - Chanock, Stephen J. A1 - Christiansen, Hans A1 - Chung, Wendy K. A1 - Claes, Kathleen B. M. A1 - Clarke, Christine L. A1 - Couch, Fergus J. A1 - Cox, Angela A1 - Cross, Simon S. A1 - Czene, Kamila A1 - Daly, Mary B. A1 - de la Hoya, Miguel A1 - Dennis, Joe A1 - Devilee, Peter A1 - Diez, Orland A1 - Dörk, Thilo A1 - Dunning, Alison M. A1 - Dwek, Miriam A1 - Eccles, Diana M. A1 - Ejlertsen, Bent A1 - Ellberg, Carolina A1 - Engel, Christoph A1 - Eriksson, Mikael A1 - Fasching, Peter A. A1 - Fletcher, Olivia A1 - Flyger, Henrik A1 - Friedman, Eitan A1 - Frost, Debra A1 - Gabrielson, Marike A1 - Gago-Dominguez, Manuela A1 - Ganz, Patricia A. A1 - Gapstur, Susan M. A1 - Garber, Judy A1 - García-Closas, Montserrat A1 - García-Sáenz, José A. A1 - Gaudet, Mia M. A1 - Giles, Graham G. A1 - Glendon, Gord A1 - Godwin, Andrew K. A1 - Goldberg, Mark S. A1 - Goldgar, David E. A1 - González-Neira, Anna A1 - Greene, Mark H. A1 - Gronwald, Jacek A1 - Guenél, Pascal A1 - Haimann, Christopher A. A1 - Hall, Per A1 - Hamann, Ute A1 - He, Wei A1 - Heyworth, Jane A1 - Hogervorst, Frans B. L. A1 - Hollestelle, Antoinette A1 - Hoover, Robert N. A1 - Hopper, John L. A1 - Hulick, Peter J. A1 - Humphreys, Keith A1 - Imyanitov, Evgeny N. A1 - Isaacs, Claudine A1 - Jakimovska, Milena A1 - Jakubowska, Anna A1 - James, Paul A. A1 - Janavicius, Ramunas A1 - Jankowitz, Rachel C. A1 - John, Esther M. A1 - Johnson, Nichola A1 - Joseph, Vijai A1 - Karlan, Beth Y. A1 - Khusnutdinova, Elza A1 - Kiiski, Johanna I. A1 - Ko, Yon-Dschun A1 - Jones, Michael E. A1 - Konstantopoulou, Irene A1 - Kristensen, Vessela N. A1 - Laitman, Yael A1 - Lambrechts, Diether A1 - Lazaro, Conxi A1 - Leslie, Goska A1 - Lester, Jenny A1 - Lesueur, Fabienne A1 - Lindström, Sara A1 - Long, Jirong A1 - Loud, Jennifer T. A1 - Lubiński, Jan A1 - Makalic, Enes A1 - Mannermaa, Arto A1 - Manoochehri, Mehdi A1 - Margolin, Sara A1 - Maurer, Tabea A1 - Mavroudis, Dimitrios A1 - McGuffog, Lesley A1 - Meindl, Alfons A1 - Menon, Usha A1 - Michailidou, Kyriaki A1 - Miller, Austin A1 - Montagna, Marco A1 - Moreno, Fernando A1 - Moserle, Lidia A1 - Mulligan, Anna Marie A1 - Nathanson, Katherine L. A1 - Neuhausen, Susan L. A1 - Nevanlinna, Heli A1 - Nevelsteen, Ines A1 - Nielsen, Finn C. A1 - Nikitina-Zake, Liene A1 - Nussbaum, Robert L. A1 - Offit, Kenneth A1 - Olah, Edith A1 - Olopade, Olufunmilayo I. A1 - Olsson, Håkan A1 - Osorio, Ana A1 - Papp, Janos A1 - Park-Simon, Tjoung-Won A1 - Parsons, Michael T. A1 - Pedersen, Inge Sokilde A1 - Peixoto, Ana A1 - Peterlongo, Paolo A1 - Pharaoh, Paul D. P. A1 - Plaseska-Karanfilska, Dijana A1 - Poppe, Bruce A1 - Presneau, Nadege A1 - Radice, Paolo A1 - Rantala, Johanna A1 - Rennert, Gad A1 - Risch, Harvey A. A1 - Saloustros, Emmanouil A1 - Sanden, Kristin A1 - Sawyer, Elinor J. A1 - Schmidt, Marjanka K. A1 - Schmutzler, Rita K. A1 - Sharma, Priyanka A1 - Shu, Xiao-Ou A1 - Simard, Jaques A1 - Singer, Christian F. A1 - Soucy, Penny A1 - Southey, Melissa C. A1 - Spinelli, John J. A1 - Spurdle, Amanda B. A1 - Stone, Jennifer A1 - Swerdlow, Anthony J. A1 - Tapper, William J. A1 - Taylor, Jack A. A1 - Teixeira, Manuel R. A1 - Terry, Mary Beth A1 - Teulé, Alex A1 - Thomassen, Mads A1 - Thöne, Kathrin A1 - Thull, Darcy L. A1 - Tischkowitz, Marc A1 - Toland, Amanda E. A1 - Torres, Diana A1 - Truong, Thérèse A1 - Tung, Nadine A1 - Vachon, Celine M. A1 - van Asperen, Christi J. A1 - van den Ouweland, Ans M. W. A1 - van Rensburg, Elizabeth J. A1 - Vega, Ana A1 - Viel, Alexandra A1 - Wang, Qin A1 - Wappenschmidt, Barbara A1 - Weitzel, Jeffrey N. A1 - Wendt, Camilla A1 - Winqvist, Robert A1 - Yang, Xiaohong R. A1 - Yannoukakos, Drakoulis A1 - Ziogas, Argyrios A1 - Kraft, Peter A1 - Antoniou, Antonis C. A1 - Zheng, Wei A1 - Easton, Douglas F. A1 - Milne, Roger L. A1 - Beesley, Jonathan A1 - Chenevix-Trench, Georgia T1 - Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer JF - Nature Communications N2 - Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer. KW - cancer KW - genetics Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-228024 VL - 10 ER - TY - JOUR A1 - Dubail, Johanne A1 - Huber, Céline A1 - Chantepie, Sandrine A1 - Sonntag, Stephan A1 - Tüysüz, Beyhan A1 - Mihci, Ercan A1 - Gordon, Christopher T. A1 - Steichen-Gersdorf, Elisabeth A1 - Amiel, Jeanne A1 - Nur, Banu A1 - Stolte-Dijkstra, Irene A1 - van Eerde, Albertien M. A1 - van Gassen, Koen L. A1 - Breugem, Corstiaan C. A1 - Stegmann, Alexander A1 - Lekszas, Caroline A1 - Maroofian, Reza A1 - Karimiani, Ehsan Ghayoor A1 - Bruneel, Arnaud A1 - Seta, Nathalie A1 - Munnich, Arnold A1 - Papy-Garcia, Dulce A1 - De La Dure-Molla, Muriel A1 - Cormier-Daire, Valérie T1 - SLC10A7 mutations cause a skeletal dysplasia with amelogenesis imperfecta mediated by GAG biosynthesis defects JF - Nature Communications N2 - Skeletal dysplasia with multiple dislocations are severe disorders characterized by dislocations of large joints and short stature. The majority of them have been linked to pathogenic variants in genes encoding glycosyltransferases, sulfotransferases or epimerases required for glycosaminoglycan synthesis. Using exome sequencing, we identify homozygous mutations in SLC10A7 in six individuals with skeletal dysplasia with multiple dislocations and amelogenesis imperfecta. SLC10A7 encodes a 10-transmembrane-domain transporter located at the plasma membrane. Functional studies in vitro demonstrate that SLC10A7 mutations reduce SLC10A7 protein expression. We generate a Slc10a7−/− mouse model, which displays shortened long bones, growth plate disorganization and tooth enamel anomalies, recapitulating the human phenotype. Furthermore, we identify decreased heparan sulfate levels in Slc10a7−/− mouse cartilage and patient fibroblasts. Finally, we find an abnormal N-glycoprotein electrophoretic profile in patient blood samples. Together, our findings support the involvement of SLC10A7 in glycosaminoglycan synthesis and specifically in skeletal development. KW - bone development KW - disease genetics KW - medical genetics Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226377 VL - 9 ER - TY - JOUR A1 - Haertle, Larissa A1 - Maierhofer, Anna A1 - Böck, Julia A1 - Lehnen, Harald A1 - Böttcher, Yvonne A1 - Blüher, Matthias A1 - Schorsch, Martin A1 - Potabattula, Ramya A1 - El Hajj, Nady A1 - Appenzeller, Silke A1 - Haaf, Thomas T1 - Hypermethylation of the non-imprinted maternal MEG3 and paternal MEST alleles is highly variable among normal individuals JF - PLoS ONE N2 - Imprinted genes show parent-specific activity (functional haploidy), which makes them particularly vulnerable to epigenetic dysregulation. Here we studied the methylation profiles of oppositely imprinted genes at single DNA molecule resolution by two independent parental allele-specific deep bisulfite sequencing (DBS) techniques. Using Roche (GSJunior) next generation sequencing technology, we analyzed the maternally imprinted MEST promoter and the paternally imprinted MEG3 intergenic (IG) differentially methylated region (DMR) in fetal cord blood, adult blood, and visceral adipose tissue. Epimutations were defined as paternal or maternal alleles with >50% aberrantly (de)methylated CpG sites, showing the wrong methylation imprint. The epimutation rates (range 2–66%) of the paternal MEST and the maternal MEG3 IG DMR allele, which should be completely unmethylated, were significantly higher than those (0–15%) of the maternal MEST and paternal MEG3 alleles, which are expected to be fully methylated. This hypermethylation of the non-imprinted allele (HNA) was independent of parental origin. Very low epimutation rates in sperm suggest that HNA occurred after fertilization. DBS with Illumina (MiSeq) technology confirmed HNA for the MEST promoter and the MEG3 IG DMR, and to a lesser extent, for the paternally imprinted secondary MEG3 promoter and the maternally imprinted PEG3 promoter. HNA leads to biallelic methylation of imprinted genes in a considerable proportion of normal body cells (somatic mosaicism) and is highly variable between individuals. We propose that during development and differentiation maintenance of differential methylation at most imprinting control regions may become to some extent redundant. The accumulation of stochastic and environmentally-induced methylation errors on the non-imprinted allele may increase epigenetic diversity between cells and individuals. KW - DNA methylation KW - genomic imprinting KW - polymerase chain reaction KW - blood KW - epigenetics KW - sequence alignment KW - sperm Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170433 VL - 12 IS - 8 ER - TY - JOUR A1 - Klughammer, Johanna A1 - Dittrich, Marcus A1 - Blom, Jochen A1 - Mitesser, Vera A1 - Vogel, Ulrich A1 - Frosch, Matthias A1 - Goesmann, Alexander A1 - Müller, Tobias A1 - Schoen, Christoph T1 - Comparative genome sequencing reveals within-host genetic changes in Neisseria meningitidis during invasive disease JF - PLoS ONE N2 - Some members of the physiological human microbiome occasionally cause life-threatening disease even in immunocompetent individuals. A prime example of such a commensal pathogen is Neisseria meningitidis, which normally resides in the human nasopharynx but is also a leading cause of sepsis and epidemic meningitis. Using N. meningitidis as model organism, we tested the hypothesis that virulence of commensal pathogens is a consequence of within host evolution and selection of invasive variants due to mutations at contingency genes, a mechanism called phase variation. In line with the hypothesis that phase variation evolved as an adaptation to colonize diverse hosts, computational comparisons of all 27 to date completely sequenced and annotated meningococcal genomes retrieved from public databases showed that contingency genes are indeed enriched for genes involved in host interactions. To assess within-host genetic changes in meningococci, we further used ultra-deep whole-genome sequencing of throat-blood strain pairs isolated from four patients suffering from invasive meningococcal disease. We detected up to three mutations per strain pair, affecting predominantly contingency genes involved in type IV pilus biogenesis. However, there was not a single (set) of mutation(s) that could invariably be found in all four pairs of strains. Phenotypic assays further showed that these genetic changes were generally not associated with increased serum resistance, higher fitness in human blood ex vivo or differences in the interaction with human epithelial and endothelial cells in vitro. In conclusion, we hypothesize that virulence of meningococci results from accidental emergence of invasive variants during carriage and without within host evolution of invasive phenotypes during disease progression in vivo. KW - blood KW - comparative genomics KW - throat KW - genetic loci KW - Neisseria meningitidis KW - genomic libraries KW - genome sequencing KW - sequence assembly tools Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-159547 VL - 12 IS - 1 ER - TY - JOUR A1 - Nanda, Indrajit A1 - Schories, Susanne A1 - Simeonov, Ivan A1 - Adolfi, Mateus Contar A1 - Du, Kang A1 - Steinlein, Claus A1 - Alsheimer, Manfred A1 - Haaf, Thomas A1 - Schartl, Manfred T1 - Evolution of the degenerated Y-chromosome of the swamp guppy, Micropoecilia picta JF - Cells N2 - The conspicuous colour sexual dimorphism of guppies has made them paradigmatic study objects for sex-linked traits and sex chromosome evolution. Both the X- and Y-chromosomes of the common guppy (Poecilia reticulata) are genetically active and homomorphic, with a large homologous part and a small sex specific region. This feature is considered to emulate the initial stage of sex chromosome evolution. A similar situation has been documented in the related Endler’s and Oropuche guppies (P. wingei, P. obscura) indicating a common origin of the Y in this group. A recent molecular study in the swamp guppy (Micropoecilia. picta) reported a low SNP density on the Y, indicating Y-chromosome deterioration. We performed a series of cytological studies on M. picta to show that the Y-chromosome is quite small compared to the X and has accumulated a high content of heterochromatin. Furthermore, the Y-chromosome stands out in displaying CpG clusters around the centromeric region. These cytological findings evidently illustrate that the Y-chromosome in M. picta is indeed highly degenerated. Immunostaining for SYCP3 and MLH1 in pachytene meiocytes revealed that a substantial part of the Y remains associated with the X. A specific MLH1 hotspot site was persistently marked at the distal end of the associated XY structure. These results unveil a landmark of a recombining pseudoautosomal region on the otherwise strongly degenerated Y chromosome of M. picta. Hormone treatments of females revealed that, unexpectedly, no sexually antagonistic color gene is Y-linked in M. picta. All these differences to the Poecilia group of guppies indicate that the trajectories associated with the evolution of sex chromosomes are not in parallel. KW - sex chromosomes KW - heterochromatin KW - Y chromosome degeneration KW - meiosis KW - synaptonemal complex KW - recombination KW - 5-methylcytosine KW - testosterone KW - sexual antagonistic genes KW - sex linked pigmentation pattern Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-267242 SN - 2073-4409 VL - 11 IS - 7 ER - TY - JOUR A1 - Prell, Andreas A1 - Sen, Mustafa Orkun A1 - Potabattula, Ramya A1 - Bernhardt, Laura A1 - Dittrich, Marcus A1 - Hahn, Thomas A1 - Schorsch, Martin A1 - Zacchini, Federica A1 - Ptak, Grazyna Ewa A1 - Niemann, Heiner A1 - Haaf, Thomas T1 - Species-specific paternal age effects and sperm methylation levels of developmentally important genes JF - Cells N2 - A growing number of sperm methylome analyses have identified genomic loci that are susceptible to paternal age effects in a variety of mammalian species, including human, bovine, and mouse. However, there is little overlap between different data sets. Here, we studied whether or not paternal age effects on the sperm epigenome have been conserved in mammalian evolution and compared methylation patterns of orthologous regulatory regions (mainly gene promoters) containing both conserved and non-conserved CpG sites in 94 human, 36 bovine, and 94 mouse sperm samples, using bisulfite pyrosequencing. We discovered three (NFKB2, RASGEF1C, and RPL6) age-related differentially methylated regions (ageDMRs) in humans, four (CHD7, HDAC11, PAK1, and PTK2B) in bovines, and three (Def6, Nrxn2, and Tbx19) in mice. Remarkably, the identified sperm ageDMRs were all species-specific. Most ageDMRs were in genomic regions with medium methylation levels and large methylation variation. Orthologous regions in species not showing this age effect were either hypermethylated (>80%) or hypomethylated (<20%). In humans and mice, ageDMRs lost methylation, whereas bovine ageDMRs gained methylation with age. Our results are in line with the hypothesis that sperm ageDMRs are in regions under epigenomic evolution and may be part of an epigenetic mechanism(s) for lineage-specific environmental adaptations and provide a solid basis for studies on downstream effects in the genes analyzed here. KW - age-related differentially methylated regions (ageDMRs) KW - bisulfite pyrosequencing KW - mammalian male germline KW - paternal age effect KW - species-specific epigenetic marks KW - sperm DNA methylation Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-262301 SN - 2073-4409 VL - 11 IS - 4 ER - TY - JOUR A1 - Liedtke, Daniel A1 - Hofmann, Christine A1 - Jakob, Franz A1 - Klopocki, Eva A1 - Graser, Stephanie T1 - Tissue-Nonspecific Alkaline Phosphatase—A Gatekeeper of Physiological Conditions in Health and a Modulator of Biological Environments in Disease JF - Biomolecules N2 - Tissue-nonspecific alkaline phosphatase (TNAP) is a ubiquitously expressed enzyme that is best known for its role during mineralization processes in bones and skeleton. The enzyme metabolizes phosphate compounds like inorganic pyrophosphate and pyridoxal-5′-phosphate to provide, among others, inorganic phosphate for the mineralization and transportable vitamin B6 molecules. Patients with inherited loss of function mutations in the ALPL gene and consequently altered TNAP activity are suffering from the rare metabolic disease hypophosphatasia (HPP). This systemic disease is mainly characterized by impaired bone and dental mineralization but may also be accompanied by neurological symptoms, like anxiety disorders, seizures, and depression. HPP characteristically affects all ages and shows a wide range of clinical symptoms and disease severity, which results in the classification into different clinical subtypes. This review describes the molecular function of TNAP during the mineralization of bones and teeth, further discusses the current knowledge on the enzyme’s role in the nervous system and in sensory perception. An additional focus is set on the molecular role of TNAP in health and on functional observations reported in common laboratory vertebrate disease models, like rodents and zebrafish. KW - TNAP KW - hypophosphatasia KW - HPP KW - zebrafish KW - mineralization KW - ALPL KW - craniosynostosis KW - teeth KW - nervous system Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-220096 SN - 2218-273X VL - 10 IS - 12 PB - MDPI ER -