Wollnik, Bernd

[["dc.bibliographiccitation.journal","Human Genetics"],["dc.contributor.author","Schmidt, Julia"],["dc.contributor.author","Goergens, Jonas"],["dc.contributor.author","Pochechueva, Tatiana"],["dc.contributor.author","Kotter, Annika"],["dc.contributor.author","Schwenzer, Niko"],["dc.contributor.author","Sitte, Maren"],["dc.contributor.author","Werner, Gesa"],["dc.contributor.author","Altmüller, Janine"],["dc.contributor.author","Thiele, Holger"],["dc.contributor.author","Nürnberg, Peter"],["dc.contributor.author","Wollnik, Bernd"],["dc.date.accessioned","2021-10-01T09:58:42Z"],["dc.date.available","2021-10-01T09:58:42Z"],["dc.date.issued","2021"],["dc.description.abstract","Abstract The highly conserved YrdC domain-containing protein (YRDC) interacts with the well-described KEOPS complex, regulating specific tRNA modifications to ensure accurate protein synthesis. Previous studies have linked the KEOPS complex to a role in promoting telomere maintenance and controlling genome integrity. Here, we report on a newborn with a severe neonatal progeroid phenotype including generalized loss of subcutaneous fat, microcephaly, growth retardation, wrinkled skin, renal failure, and premature death at the age of 12 days. By trio whole-exome sequencing, we identified a novel homozygous missense mutation, c.662T > C, in YRDC affecting an evolutionary highly conserved amino acid (p.Ile221Thr). Functional characterization of patient-derived dermal fibroblasts revealed that this mutation impairs YRDC function and consequently results in reduced t 6 A modifications of tRNAs. Furthermore, we established and performed a novel and highly sensitive 3-D Q-FISH analysis based on single-telomere detection to investigate the impact of YRDC on telomere maintenance. This analysis revealed significant telomere shortening in YRDC-mutant cells. Moreover, single-cell RNA sequencing analysis of YRDC-mutant fibroblasts revealed significant transcriptome-wide changes in gene expression, specifically enriched for genes associated with processes involved in DNA repair. We next examined the DNA damage response of patient’s dermal fibroblasts and detected an increased susceptibility to genotoxic agents and a global DNA double-strand break repair defect. Thus, our data suggest that YRDC may affect the maintenance of genomic stability. Together, our findings indicate that biallelic variants in YRDC result in a developmental disorder with progeroid features and might be linked to increased genomic instability and telomere shortening."],["dc.identifier.doi","10.1007/s00439-021-02347-3"],["dc.identifier.pii","2347"],["dc.identifier.pmid","34545459"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/90122"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/347"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/406"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-469"],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation","SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz"],["dc.relation","SFB 1002 | A09: Lokale molekulare Nanodomänen-Regulation der kardialen Ryanodin-Rezeptor-Funktion"],["dc.relation","SFB 1002 | S02: Hochauflösende Fluoreszenzmikroskopie und integrative Datenanalyse"],["dc.relation.eissn","1432-1203"],["dc.relation.issn","0340-6717"],["dc.relation.workinggroup","RG Lehnart"],["dc.relation.workinggroup","RG Wollnik"],["dc.rights","CC BY 4.0"],["dc.title","Biallelic variants in YRDC cause a developmental disorder with progeroid features"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","591"],["dc.bibliographiccitation.issue","3"],["dc.bibliographiccitation.journal","Human Mutation"],["dc.bibliographiccitation.lastpage","599"],["dc.bibliographiccitation.volume","41"],["dc.contributor.author","Yigit, Gökhan"],["dc.contributor.author","Saida, Ken"],["dc.contributor.author","DeMarzo, Danielle"],["dc.contributor.author","Miyake, Noriko"],["dc.contributor.author","Fujita, Atsushi"],["dc.contributor.author","Yang Tan, Tiong"],["dc.contributor.author","White, Susan M."],["dc.contributor.author","Wadley, Alexandrea"],["dc.contributor.author","Toliat, Mohammad R."],["dc.contributor.author","Motameny, Susanne"],["dc.contributor.author","Franitza, Marek"],["dc.contributor.author","Stutterd, Chloe A."],["dc.contributor.author","Chong, Pin F."],["dc.contributor.author","Kira, Ryutaro"],["dc.contributor.author","Sengoku, Toru"],["dc.contributor.author","Ogata, Kazuhiro"],["dc.contributor.author","Guillen Sacoto, Maria J."],["dc.contributor.author","Fresen, Christine"],["dc.contributor.author","Beck, Bodo B."],["dc.contributor.author","Nürnberg, Peter"],["dc.contributor.author","Dieterich, Christoph"],["dc.contributor.author","Wollnik, Bernd"],["dc.contributor.author","Matsumoto, Naomichi"],["dc.contributor.author","Altmüller, Janine"],["dc.date.accessioned","2020-12-10T14:06:39Z"],["dc.date.available","2020-12-10T14:06:39Z"],["dc.date.issued","2019"],["dc.description.abstract","RHOA is a member of the Rho family of GTPases that are involved in fundamental cellular processes including cell adhesion, migration, and proliferation. RHOA can stimulate the formation of stress fibers and focal adhesions and is a key regulator of actomyosin dynamics in various tissues. In a Genematcher-facilitated collaboration, we were able to identify four unrelated individuals with a specific phenotype characterized by hypopigmented areas of the skin, dental anomalies, body asymmetry, and limb length discrepancy due to hemihypotrophy of one half of the body, as well as brain magnetic resonance imaging (MRI) anomalies. Using whole-exome and ultra-deep amplicon sequencing and comparing genomic data of affected and unaffected areas of the skin, we discovered that all four individuals carried the identical RHOA missense variant, c.139G>A; p.Glu47Lys, in a postzygotic state. Molecular modeling and in silico analysis of the affected p.Glu47Lys residue in RHOA indicated that this exchange is predicted to specifically alter the interaction of RHOA with its downstream effectors containing a PKN-type binding domain and thereby disrupts its ability to activate signaling. Our findings indicate that the recurrent postzygotic RHOA missense variant p.Glu47Lys causes a specific mosaic disorder in humans."],["dc.description.sponsorship","AMED http://dx.doi.org/10.13039/100009619"],["dc.description.sponsorship","Deutsche Forschungsgemeinschaft http://dx.doi.org/10.13039/501100001659"],["dc.description.sponsorship","JSPS http://dx.doi.org/10.13039/501100001691"],["dc.description.sponsorship","Takeda Science Foundation http://dx.doi.org/10.13039/100007449"],["dc.description.sponsorship","Ministry of Health, Labour and Welfare http://dx.doi.org/10.13039/501100003478"],["dc.identifier.doi","10.1002/humu.23964"],["dc.identifier.eissn","1098-1004"],["dc.identifier.issn","1059-7794"],["dc.identifier.pmid","31821646"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/17077"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/69974"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/10"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-354"],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation.eissn","1098-1004"],["dc.relation.issn","1059-7794"],["dc.relation.orgunit","Universitätsmedizin Göttingen"],["dc.relation.workinggroup","RG Wollnik"],["dc.rights","CC BY-NC 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by-nc/4.0"],["dc.subject.ddc","610"],["dc.title","The recurrent postzygotic pathogenic variant p.Glu47Lys in RHOA causes a novel recognizable neuroectodermal phenotype"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1454"],["dc.bibliographiccitation.issue","10"],["dc.bibliographiccitation.journal","Human Mutation"],["dc.bibliographiccitation.lastpage","1471"],["dc.bibliographiccitation.volume","43"],["dc.contributor.affiliation","Bögershausen, Nina; 1\r\nInstitute of Human Genetics\r\nUniversity Medical Center Göttingen\r\nGöttingen Germany"],["dc.contributor.affiliation","Krawczyk, Hannah E.; 1\r\nInstitute of Human Genetics\r\nUniversity Medical Center Göttingen\r\nGöttingen Germany"],["dc.contributor.affiliation","Jamra, Rami A.; 2\r\nInstitute of Human Genetics\r\nUniversity of Leipzig Medical Center\r\nLeipzig Germany"],["dc.contributor.affiliation","Lin, Sheng‐Jia; 3\r\nGenes & Human Disease Research Program\r\nOklahoma Medical Research Foundation\r\nOklahoma City Oklahoma USA"],["dc.contributor.affiliation","Yigit, Gökhan; 1\r\nInstitute of Human Genetics\r\nUniversity Medical Center Göttingen\r\nGöttingen Germany"],["dc.contributor.affiliation","Hüning, Irina; 4\r\nInstitut für Humangenetik\r\nUniversitätsklinikum Schleswig‐Holstein\r\nLübeck Germany"],["dc.contributor.affiliation","Polo, Anna M.; 5\r\nMVZ Labor Krone\r\nFilialpraxis für Humangenetik\r\nBielefeld Germany"],["dc.contributor.affiliation","Vona, Barbara; 1\r\nInstitute of Human Genetics\r\nUniversity Medical Center Göttingen\r\nGöttingen Germany"],["dc.contributor.affiliation","Huang, Kevin; 3\r\nGenes & Human Disease Research Program\r\nOklahoma Medical Research Foundation\r\nOklahoma City Oklahoma USA"],["dc.contributor.affiliation","Schmidt, Julia; 1\r\nInstitute of Human Genetics\r\nUniversity Medical Center Göttingen\r\nGöttingen Germany"],["dc.contributor.affiliation","Altmüller, Janine; 7\r\nCologne Center for Genomics (CCG), Faculty of Medicine and University Hospital Cologne\r\nUniversity of Cologne\r\nCologne Germany"],["dc.contributor.affiliation","Luppe, Johannes; 2\r\nInstitute of Human Genetics\r\nUniversity of Leipzig Medical Center\r\nLeipzig Germany"],["dc.contributor.affiliation","Platzer, Konrad; 2\r\nInstitute of Human Genetics\r\nUniversity of Leipzig Medical Center\r\nLeipzig Germany"],["dc.contributor.affiliation","Dörgeloh, Beate B.; 10\r\nDepartment of Pediatric Hematology and Oncology\r\nHannover Medical School\r\nHannover Germany"],["dc.contributor.affiliation","Busche, Andreas; 11\r\nInstitut für Humangenetik\r\nWestfälische Wilhelms‐Universität Münster\r\nMünster Germany"],["dc.contributor.affiliation","Biskup, Saskia; 12\r\nCeGaT GmbH\r\nCenter for Genomics and Transcriptomics\r\nTübingen Germany"],["dc.contributor.affiliation","Mendes, Marisa I.; 13\r\nLaboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology and Metabolism, Amsterdam Neuroscience\r\nAmsterdam UMC\r\nAmsterdam Netherlands"],["dc.contributor.affiliation","Smith, Desiree E. C.; 13\r\nLaboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology and Metabolism, Amsterdam Neuroscience\r\nAmsterdam UMC\r\nAmsterdam Netherlands"],["dc.contributor.affiliation","Salomons, Gajja S.; 13\r\nLaboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology and Metabolism, Amsterdam Neuroscience\r\nAmsterdam UMC\r\nAmsterdam Netherlands"],["dc.contributor.affiliation","Zibat, Arne; 1\r\nInstitute of Human Genetics\r\nUniversity Medical Center Göttingen\r\nGöttingen Germany"],["dc.contributor.affiliation","Bültmann, Eva; 14\r\nInstitute of Diagnostic and Interventional Neuroradiology\r\nHannover Medical School\r\nHannover Germany"],["dc.contributor.affiliation","Nürnberg, Peter; 7\r\nCologne Center for Genomics (CCG), Faculty of Medicine and University Hospital Cologne\r\nUniversity of Cologne\r\nCologne Germany"],["dc.contributor.affiliation","Spielmann, Malte; 4\r\nInstitut für Humangenetik\r\nUniversitätsklinikum Schleswig‐Holstein\r\nLübeck Germany"],["dc.contributor.affiliation","Lemke, Johannes R.; 2\r\nInstitute of Human Genetics\r\nUniversity of Leipzig Medical Center\r\nLeipzig Germany"],["dc.contributor.affiliation","Li, Yun; 1\r\nInstitute of Human Genetics\r\nUniversity Medical Center Göttingen\r\nGöttingen Germany"],["dc.contributor.affiliation","Zenker, Martin; 16\r\nInstitute of Human Genetics\r\nOtto‐von‐Guericke University Magdeburg\r\nMagdeburg Germany"],["dc.contributor.affiliation","Varshney, Gaurav K.; 3\r\nGenes & Human Disease Research Program\r\nOklahoma Medical Research Foundation\r\nOklahoma City Oklahoma USA"],["dc.contributor.affiliation","Hillen, Hauke S.; 17\r\nResearch Group Structure and Function of Molecular Machines\r\nMax Planck Institute for Multidisciplinary Sciences\r\nGöttingen Germany"],["dc.contributor.affiliation","Kratz, Christian P.; 10\r\nDepartment of Pediatric Hematology and Oncology\r\nHannover Medical School\r\nHannover Germany"],["dc.contributor.author","Bögershausen, Nina"],["dc.contributor.author","Krawczyk, Hannah E."],["dc.contributor.author","Jamra, Rami A."],["dc.contributor.author","Lin, Sheng‐Jia"],["dc.contributor.author","Yigit, Gökhan"],["dc.contributor.author","Hüning, Irina"],["dc.contributor.author","Polo, Anna M."],["dc.contributor.author","Vona, Barbara"],["dc.contributor.author","Huang, Kevin"],["dc.contributor.author","Schmidt, Julia"],["dc.contributor.author","Altmüller, Janine"],["dc.contributor.author","Luppe, Johannes"],["dc.contributor.author","Platzer, Konrad"],["dc.contributor.author","Dörgeloh, Beate B."],["dc.contributor.author","Busche, Andreas"],["dc.contributor.author","Biskup, Saskia"],["dc.contributor.author","Mendes, Marisa I."],["dc.contributor.author","Smith, Desiree E. C."],["dc.contributor.author","Salomons, Gajja S."],["dc.contributor.author","Zibat, Arne"],["dc.contributor.author","Bültmann, Eva"],["dc.contributor.author","Nürnberg, Peter"],["dc.contributor.author","Spielmann, Malte"],["dc.contributor.author","Lemke, Johannes R."],["dc.contributor.author","Li, Yun"],["dc.contributor.author","Zenker, Martin"],["dc.contributor.author","Varshney, Gaurav K."],["dc.contributor.author","Hillen, Hauke S."],["dc.contributor.author","Kratz, Christian P."],["dc.contributor.author","Wollnik, Bernd"],["dc.date.accessioned","2022-11-28T09:45:52Z"],["dc.date.available","2022-11-28T09:45:52Z"],["dc.date.issued","2022-07-21"],["dc.date.updated","2022-11-27T10:11:29Z"],["dc.description.abstract","Based on the identification of novel variants in aminoacyl‐tRNA synthetase (ARS) genes WARS1 and SARS1, the authors define an emerging disease spectrum related to all type 1 ARS genes: aminoacyl‐tRNA synthetase‐related developmental disorders with or without microcephaly (ARS‐DDM).\r\n\r\nimage"],["dc.description.abstract","Aminoacylation of transfer RNA (tRNA) is a key step in protein biosynthesis, carried out by highly specific aminoacyl-tRNA synthetases (ARSs). ARSs have been implicated in autosomal dominant and autosomal recessive human disorders. Autosomal dominant variants in tryptophanyl-tRNA synthetase 1 (WARS1) are known to cause distal hereditary motor neuropathy and Charcot-Marie-Tooth disease, but a recessively inherited phenotype is yet to be clearly defined. Seryl-tRNA synthetase 1 (SARS1) has rarely been implicated in an autosomal recessive developmental disorder. Here, we report five individuals with biallelic missense variants in WARS1 or SARS1, who presented with an overlapping phenotype of microcephaly, developmental delay, intellectual disability, and brain anomalies. Structural mapping showed that the SARS1 variant is located directly within the enzyme's active site, most likely diminishing activity, while the WARS1 variant is located in the N-terminal domain. We further characterize the identified WARS1 variant by showing that it negatively impacts protein abundance and is unable to rescue the phenotype of a CRISPR/Cas9 wars1 knockout zebrafish model. In summary, we describe two overlapping autosomal recessive syndromes caused by variants in WARS1 and SARS1, present functional insights into the pathogenesis of the WARS1-related syndrome and define an emerging disease spectrum: ARS-related developmental disorders with or without microcephaly."],["dc.description.sponsorship","Deutsches Zentrum für Herz‐Kreislaufforschung http://dx.doi.org/10.13039/100010447"],["dc.description.sponsorship","Deutsche Forschungsgemeinschaft http://dx.doi.org/10.13039/501100001659"],["dc.description.sponsorship","Presbyterian Health Foundation http://dx.doi.org/10.13039/100001298"],["dc.description.sponsorship","University Medical Center Göttingen"],["dc.description.sponsorship","Oklahoma Medical Research Foundation http://dx.doi.org/10.13039/100008907"],["dc.identifier.doi","10.1002/humu.24430"],["dc.identifier.pmid","35790048"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/117321"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/517"],["dc.identifier.url","https://sfb1190.med.uni-goettingen.de/production/literature/publications/180"],["dc.identifier.url","https://for2848.gwdguser.de/literature/publications/34"],["dc.language.iso","en"],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation","SFB 1190: Transportmaschinen und Kontaktstellen zellulärer Kompartimente"],["dc.relation","FOR 2848: Architektur und Heterogenität der inneren mitochondrialen Membran auf der Nanoskala"],["dc.relation","FOR 2848 | St01: Structure and distribution of ribosomes at the inner mitochondrial membrane"],["dc.relation.eissn","1098-1004"],["dc.relation.issn","1059-7794"],["dc.relation.workinggroup","RG Wollnik"],["dc.relation.workinggroup","RG Hillen (Structure and Function of Molecular Machines)"],["dc.rights","CC BY-NC-ND 4.0"],["dc.title","WARS1 and SARS1: Two tRNA synthetases implicated in autosomal recessive microcephaly"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1363"],["dc.bibliographiccitation.issue","11"],["dc.bibliographiccitation.journal","Human Genetics"],["dc.bibliographiccitation.lastpage","1379"],["dc.bibliographiccitation.volume","139"],["dc.contributor.author","Ufartes, Roser"],["dc.contributor.author","Berger, Hanna"],["dc.contributor.author","Till, Katharina"],["dc.contributor.author","Salinas, Gabriela"],["dc.contributor.author","Sturm, Marc"],["dc.contributor.author","Altmüller, Janine"],["dc.contributor.author","Nürnberg, Peter"],["dc.contributor.author","Thiele, Holger"],["dc.contributor.author","Funke, Rudolf"],["dc.contributor.author","Apeshiotis, Neophytos"],["dc.contributor.author","Langen, Hendrik"],["dc.contributor.author","Wollnik, Bernd"],["dc.contributor.author","Borchers, Annette"],["dc.contributor.author","Pauli, Silke"],["dc.date.accessioned","2020-12-10T14:10:38Z"],["dc.date.available","2020-12-10T14:10:38Z"],["dc.date.issued","2020"],["dc.description.abstract","We report truncating de novo variants in specific exons of FBRSL1 in three unrelated children with an overlapping syndromic phenotype with respiratory insufficiency, postnatal growth restriction, microcephaly, global developmental delay and other malformations. The function of FBRSL1 is largely unknown. Interestingly, mutations in the FBRSL1 paralogue AUTS2 lead to an intellectual disability syndrome (AUTS2 syndrome). We determined human FBRSL1 transcripts and describe protein-coding forms by Western blot analysis as well as the cellular localization by immunocytochemistry stainings. All detected mutations affect the two short N-terminal isoforms, which show a ubiquitous expression in fetal tissues. Next, we performed a Fbrsl1 knockdown in Xenopus laevis embryos to explore the role of Fbrsl1 during development and detected craniofacial abnormalities and a disturbance in neurite outgrowth. The aberrant phenotype in Xenopus laevis embryos could be rescued with a human N-terminal isoform, while the long isoform and the N-terminal isoform containing the mutation p.Gln163* isolated from a patient could not rescue the craniofacial defects caused by Fbrsl1 depletion. Based on these data, we propose that the disruption of the validated N-terminal isoforms of FBRSL1 at critical timepoints during embryogenesis leads to a hitherto undescribed complex neurodevelopmental syndrome."],["dc.identifier.doi","10.1007/s00439-020-02175-x"],["dc.identifier.pmid","32424618"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/70825"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/184"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-354"],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation.workinggroup","RG Wollnik"],["dc.rights","CC BY 4.0"],["dc.title","De novo mutations in FBRSL1 cause a novel recognizable malformation and intellectual disability syndrome"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","e14277"],["dc.bibliographiccitation.firstpage","1"],["dc.bibliographiccitation.journal","eLife"],["dc.bibliographiccitation.lastpage","30"],["dc.bibliographiccitation.volume","5"],["dc.contributor.author","Hatzold, Julia"],["dc.contributor.author","Beleggia, Filippo"],["dc.contributor.author","Herzig, Hannah"],["dc.contributor.author","Altmüller, Janine"],["dc.contributor.author","Nürnberg, Peter"],["dc.contributor.author","Bloch, Wilhelm"],["dc.contributor.author","Wollnik, Bernd"],["dc.contributor.author","Hammerschmidt, Matthias"],["dc.date.accessioned","2016-09-19T06:22:44Z"],["dc.date.accessioned","2021-10-27T13:20:44Z"],["dc.date.available","2016-09-19T06:22:44Z"],["dc.date.available","2021-10-27T13:20:44Z"],["dc.date.issued","2016"],["dc.description.abstract","The molecular pathways underlying tumor suppression are incompletely understood. Here, we identify cooperative non-cell-autonomous functions of a single gene that together provide a novel mechanism of tumor suppression in basal keratinocytes of zebrafish embryos. A loss-of-function mutation in atp1b1a, encoding the beta subunit of a Na,K-ATPase pump, causes edema and epidermal malignancy. Strikingly, basal cell carcinogenesis only occurs when Atp1b1a function is compromised in both the overlying periderm (resulting in compromised epithelial polarity and adhesiveness) and in kidney and heart (resulting in hypotonic stress). Blockade of the ensuing PI3K-AKT-mTORC1-NFκB-MMP9 pathway activation in basal cells, as well as systemic isotonicity, prevents malignant transformation. Our results identify hypotonic stress as a (previously unrecognized) contributor to tumor development and establish a novel paradigm of tumor suppression."],["dc.identifier.doi","10.7554/eLife.14277"],["dc.identifier.fs","621002"],["dc.identifier.gro","3145171"],["dc.identifier.pmid","27240166"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/13679"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/91980"],["dc.language.iso","en"],["dc.notes.intern","Migrated from goescholar"],["dc.notes.status","final"],["dc.relation.euproject","ZF-HEALTH"],["dc.relation.issn","2050-084X"],["dc.relation.orgunit","Universitätsmedizin Göttingen"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.subject","Na/K-ATPase; basal cell carcinogenesis; cancer biology; developmental biology; epithelial polarity; stem cells; zebrafish"],["dc.title","Tumor suppression in basal keratinocytes via dual non-cell-autonomous functions of a Na,K-ATPase beta subunit"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","549"],["dc.bibliographiccitation.issue","6"],["dc.bibliographiccitation.journal","Journal of Medical Genetics"],["dc.bibliographiccitation.lastpage","553"],["dc.bibliographiccitation.volume","59"],["dc.contributor.affiliation","Yigit, Gökhan; \r\n1\r\nInstitute of Human Genetics, University Medical Center Göttingen, Gottingen, Germany"],["dc.contributor.affiliation","Sheffer, Ruth; \r\n2\r\nDepartment of Human Genetics, Hadassah University Hospital, Jerusalem, Israel"],["dc.contributor.affiliation","Daana, Muhannad; \r\n3\r\nChild Development Institute, Clalit Health Services, Tel Aviv, Israel"],["dc.contributor.affiliation","Li, Yun; \r\n1\r\nInstitute of Human Genetics, University Medical Center Göttingen, Gottingen, Germany"],["dc.contributor.affiliation","Kaygusuz, Emrah; \r\n1\r\nInstitute of Human Genetics, University Medical Center Göttingen, Gottingen, Germany"],["dc.contributor.affiliation","Mor-Shakad, Hagar; \r\n2\r\nDepartment of Human Genetics, Hadassah University Hospital, Jerusalem, Israel"],["dc.contributor.affiliation","Altmüller, Janine; \r\n5\r\nCologne Center for Genomics (CCG), University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany"],["dc.contributor.affiliation","Nürnberg, Peter; \r\n5\r\nCologne Center for Genomics (CCG), University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany"],["dc.contributor.affiliation","Douiev, Liza; \r\n2\r\nDepartment of Human Genetics, Hadassah University Hospital, Jerusalem, Israel"],["dc.contributor.affiliation","Kaulfuss, Silke; \r\n1\r\nInstitute of Human Genetics, University Medical Center Göttingen, Gottingen, Germany"],["dc.contributor.affiliation","Burfeind, Peter; \r\n1\r\nInstitute of Human Genetics, University Medical Center Göttingen, Gottingen, Germany"],["dc.contributor.affiliation","Wollnik, Bernd; \r\n1\r\nInstitute of Human Genetics, University Medical Center Göttingen, Gottingen, Germany"],["dc.contributor.affiliation","Brockmann, Knut; \r\n7\r\nInterdisciplinary Pediatric Center for Children with Developmental Disabilities and Severe Chronic Disorders, University Medical Center Göttingen, Gottingen, Germany"],["dc.contributor.author","Yigit, Gökhan"],["dc.contributor.author","Sheffer, Ruth"],["dc.contributor.author","Daana, Muhannad"],["dc.contributor.author","Li, Yun"],["dc.contributor.author","Kaygusuz, Emrah"],["dc.contributor.author","Mor-Shakad, Hagar"],["dc.contributor.author","Altmüller, Janine"],["dc.contributor.author","Nürnberg, Peter"],["dc.contributor.author","Douiev, Liza"],["dc.contributor.author","Brockmann, Knut"],["dc.contributor.author","Kaulfuss, Silke"],["dc.contributor.author","Burfeind, Peter"],["dc.contributor.author","Wollnik, Bernd"],["dc.date.accessioned","2021-07-05T14:57:45Z"],["dc.date.available","2021-07-05T14:57:45Z"],["dc.date.issued","2021"],["dc.date.updated","2022-05-21T14:18:33Z"],["dc.description.abstract","Background Developmental and epileptic encephalopathies (DEEs) represent a group of severe neurological disorders characterised by an onset of refractory seizures during infancy or early childhood accompanied by psychomotor developmental delay or regression. DEEs are genetically heterogeneous with, to date, more than 80 different genetic subtypes including DEE31 caused by heterozygous missense variants in DNM1 . Methods We performed a detailed clinical characterisation of two unrelated patients with DEE and used whole-exome sequencing to identify causative variants in these individuals. The identified variants were tested for cosegregation in the respective families. Results We excluded pathogenic variants in known, DEE-associated genes. We identified homozygous nonsense variants, c.97C>T; p.(Gln33 ) in family 1 and c.850C>T; p.(Gln284 ) in family 2, in the DNM1 gene, indicating that biallelic, loss-of-function pathogenic variants in DNM1 cause DEE. Conclusion Our finding that homozygous, loss-of-function variants in DNM1 cause DEE expands the spectrum of pathogenic variants in DNM1 . All parents who were heterozygous carriers of the identified loss-of-function variants were healthy and did not show any clinical symptoms, indicating that the type of mutation in DNM1 determines the pattern of inheritance."],["dc.description.abstract","Background Developmental and epileptic encephalopathies (DEEs) represent a group of severe neurological disorders characterised by an onset of refractory seizures during infancy or early childhood accompanied by psychomotor developmental delay or regression. DEEs are genetically heterogeneous with, to date, more than 80 different genetic subtypes including DEE31 caused by heterozygous missense variants in DNM1 . Methods We performed a detailed clinical characterisation of two unrelated patients with DEE and used whole-exome sequencing to identify causative variants in these individuals. The identified variants were tested for cosegregation in the respective families. Results We excluded pathogenic variants in known, DEE-associated genes. We identified homozygous nonsense variants, c.97C>T; p.(Gln33 ) in family 1 and c.850C>T; p.(Gln284 ) in family 2, in the DNM1 gene, indicating that biallelic, loss-of-function pathogenic variants in DNM1 cause DEE. Conclusion Our finding that homozygous, loss-of-function variants in DNM1 cause DEE expands the spectrum of pathogenic variants in DNM1 . All parents who were heterozygous carriers of the identified loss-of-function variants were healthy and did not show any clinical symptoms, indicating that the type of mutation in DNM1 determines the pattern of inheritance."],["dc.identifier","34172529"],["dc.identifier.doi","10.1136/jmedgenet-2021-107769"],["dc.identifier.pmid","34172529"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/87729"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/396"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/311"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-441"],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation","SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz"],["dc.relation","SFB 1002 | D02: Neue Mechanismen der genomischen Instabilität bei Herzinsuffizienz"],["dc.relation.eissn","1468-6244"],["dc.relation.issn","0022-2593"],["dc.relation.workinggroup","RG Wollnik"],["dc.rights.uri","http://creativecommons.org/licenses/by-nc/4.0/"],["dc.title","Loss-of-function variants in DNM1 cause a specific form of developmental and epileptic encephalopathy only in biallelic state"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.journal","Frontiers in Cell and Developmental Biology"],["dc.bibliographiccitation.volume","10"],["dc.contributor.affiliation","Schmidt, Julia; \n1\nInstitute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany"],["dc.contributor.affiliation","Dreha-Kulaczewski, Steffi; \n2\nDepartment of Pediatics and Adolescent Medicine, University Medical Center Göttingen, Göttingen, Germany"],["dc.contributor.affiliation","Zafeiriou, Maria-Patapia; \n3\nInstitute of Pharmacology and Toxicology, University Medical Center Göttingen, Göttingen, Germany"],["dc.contributor.affiliation","Schreiber, Marie-Kristin; \n3\nInstitute of Pharmacology and Toxicology, University Medical Center Göttingen, Göttingen, Germany"],["dc.contributor.affiliation","Wilken, Bernd; \n6\nDepartment of Pediatric Neurology, Klinikum Kassel, Kassel, Germany"],["dc.contributor.affiliation","Funke, Rudolf; \n6\nDepartment of Pediatric Neurology, Klinikum Kassel, Kassel, Germany"],["dc.contributor.affiliation","Neuhofer, Christiane M; \n1\nInstitute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany"],["dc.contributor.affiliation","Altmüller, Janine; \n9\nCologne Center for Genomics (CCG), University of Cologne, Faculty of Medicine, University Hospital Cologne, Cologne, Germany"],["dc.contributor.affiliation","Thiele, Holger; \n9\nCologne Center for Genomics (CCG), University of Cologne, Faculty of Medicine, University Hospital Cologne, Cologne, Germany"],["dc.contributor.affiliation","Nürnberg, Peter; \n9\nCologne Center for Genomics (CCG), University of Cologne, Faculty of Medicine, University Hospital Cologne, Cologne, Germany"],["dc.contributor.affiliation","Biskup, Saskia; \n12\nCeGaT GmbH, Center for Genomics and Transcriptomics, Tübingen, Germany"],["dc.contributor.affiliation","Li, Yun; \n1\nInstitute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany"],["dc.contributor.affiliation","Zimmermann, Wolfram Hubertus; \n3\nInstitute of Pharmacology and Toxicology, University Medical Center Göttingen, Göttingen, Germany"],["dc.contributor.affiliation","Kaulfuß, Silke; \n1\nInstitute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany"],["dc.contributor.affiliation","Yigit, Gökhan; \n1\nInstitute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany"],["dc.contributor.affiliation","Wollnik, Bernd; \n1\nInstitute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany"],["dc.contributor.author","Schmidt, Julia"],["dc.contributor.author","Dreha-Kulaczewski, Steffi"],["dc.contributor.author","Zafeiriou, Maria Patapia"],["dc.contributor.author","Schreiber, Marie-Kristin"],["dc.contributor.author","Wilken, Bernd"],["dc.contributor.author","Funke, Rudolf"],["dc.contributor.author","Neuhofer, Christiane M"],["dc.contributor.author","Altmüller, Janine"],["dc.contributor.author","Thiele, Holger"],["dc.contributor.author","Nürnberg, Peter"],["dc.contributor.author","Biskup, Saskia"],["dc.contributor.author","Li, Yun"],["dc.contributor.author","Zimmermann, Wolfram-Hubertus"],["dc.contributor.author","Kaulfuß, Silke"],["dc.contributor.author","Yigit, Gökhan"],["dc.contributor.author","Wollnik, Bernd"],["dc.date.accessioned","2022-11-30T10:25:07Z"],["dc.date.available","2022-11-30T10:25:07Z"],["dc.date.issued","2022-11-16"],["dc.date.updated","2022-11-30T08:55:41Z"],["dc.description.abstract","STAG2 is a component of the large, evolutionarily highly conserved cohesin complex, which has been linked to various cellular processes like genome organization, DNA replication, gene expression, heterochromatin formation, sister chromatid cohesion, and DNA repair. A wide spectrum of germline variants in genes encoding subunits or regulators of the cohesin complex have previously been identified to cause distinct but phenotypically overlapping multisystem developmental disorders belonging to the group of cohesinopathies. Pathogenic variants in STAG2 have rarely been implicated in an X-linked cohesinopathy associated with undergrowth, developmental delay, and dysmorphic features. Here, we describe for the first time a mosaic STAG2 variant in an individual with developmental delay, microcephaly, and hemihypotrophy of the right side. We characterized the grade of mosaicism by deep sequencing analysis on DNA extracted from EDTA blood, urine and buccal swabs. Furthermore, we report an additional female with a novel de novo splice variant in STAG2. Interestingly, both individuals show supernumerary nipples, a feature that has not been reported associated to STAG2 before. Remarkably, additional analysis of STAG2 transcripts in both individuals showed only wildtype transcripts, even after blockage of nonsense-mediated decay using puromycin in blood lymphocytes. As the phenotype of STAG2-associated cohesinopathies is dominated by global developmental delay, severe microcephaly, and brain abnormalities, we investigated the expression of STAG2 and other related components of the cohesin complex during Bioengineered Neuronal Organoids (BENOs) generation by RNA sequencing. Interestingly, we observed a prominent expression of STAG2, especially between culture days 0 and 15, indicating an essential function of STAG2 in early brain development. In summary, we expand the genotypic and phenotypic spectrum of STAG2-associated cohesinopathies and show that BENOs represent a promising model to gain further insights into the critical role of STAG2 in the complex process of nervous system development."],["dc.identifier.doi","10.3389/fcell.2022.1025332"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/117901"],["dc.language.iso","en"],["dc.relation.eissn","2296-634X"],["dc.rights.uri","http://creativecommons.org/licenses/by/4.0/"],["dc.title","Somatic mosaicism in STAG2-associated cohesinopathies: Expansion of the genotypic and phenotypic spectrum"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","559"],["dc.bibliographiccitation.issue","5-6"],["dc.bibliographiccitation.journal","Clinical Genetics"],["dc.bibliographiccitation.lastpage","564"],["dc.bibliographiccitation.volume","101"],["dc.contributor.affiliation","Gönenc, Ipek Ilgin; 1\r\nInstitute of Human Genetics\r\nUniversity Medical Center Göttingen\r\nGöttingen Germany"],["dc.contributor.affiliation","Elcioglu, Nursel H.; 2\r\nDepartment of Pediatric Genetics\r\nMarmara University Medical School\r\nIstanbul Turkey"],["dc.contributor.affiliation","Martinez Grijalva, Carolina; 1\r\nInstitute of Human Genetics\r\nUniversity Medical Center Göttingen\r\nGöttingen Germany"],["dc.contributor.affiliation","Aras, Seda; 4\r\nDepartment of Pediatric Haematology and Oncology\r\nMarmara University Medical School\r\nIstanbul Turkey"],["dc.contributor.affiliation","Großmann, Nadine; 1\r\nInstitute of Human Genetics\r\nUniversity Medical Center Göttingen\r\nGöttingen Germany"],["dc.contributor.affiliation","Praulich, Inka; 1\r\nInstitute of Human Genetics\r\nUniversity Medical Center Göttingen\r\nGöttingen Germany"],["dc.contributor.affiliation","Altmüller, Janine; 5\r\nCologne Center for Genomics (CCG)\r\nUniversity of Cologne\r\nCologne Germany"],["dc.contributor.affiliation","Kaulfuß, Silke; 1\r\nInstitute of Human Genetics\r\nUniversity Medical Center Göttingen\r\nGöttingen Germany"],["dc.contributor.affiliation","Li, Yun; 1\r\nInstitute of Human Genetics\r\nUniversity Medical Center Göttingen\r\nGöttingen Germany"],["dc.contributor.affiliation","Nürnberg, Peter; 5\r\nCologne Center for Genomics (CCG)\r\nUniversity of Cologne\r\nCologne Germany"],["dc.contributor.affiliation","Burfeind, Peter; 1\r\nInstitute of Human Genetics\r\nUniversity Medical Center Göttingen\r\nGöttingen Germany"],["dc.contributor.affiliation","Yigit, Gökhan; 1\r\nInstitute of Human Genetics\r\nUniversity Medical Center Göttingen\r\nGöttingen Germany"],["dc.contributor.author","Gönenc, Ipek Ilgin"],["dc.contributor.author","Elcioglu, Nursel H."],["dc.contributor.author","Martinez Grijalva, Carolina"],["dc.contributor.author","Aras, Seda"],["dc.contributor.author","Großmann, Nadine"],["dc.contributor.author","Praulich, Inka"],["dc.contributor.author","Altmüller, Janine"],["dc.contributor.author","Kaulfuß, Silke"],["dc.contributor.author","Li, Yun"],["dc.contributor.author","Nürnberg, Peter"],["dc.contributor.author","Wollnik, Bernd"],["dc.contributor.author","Burfeind, Peter"],["dc.contributor.author","Yigit, Gökhan"],["dc.date.accessioned","2022-04-01T10:00:24Z"],["dc.date.available","2022-04-01T10:00:24Z"],["dc.date.issued","2022"],["dc.date.updated","2022-06-14T22:49:33Z"],["dc.description.abstract","Abstract Bloom syndrome (BS) is an autosomal recessive disorder with characteristic clinical features of primary microcephaly, growth deficiency, cancer predisposition, and immunodeficiency. Here, we report the clinical and molecular findings of eight patients from six families diagnosed with BS. We identified causative pathogenic variants in all families including three different variants in BLM and one variant in RMI1. The homozygous c.581_582delTT;p.Phe194 and c.3164G>C;p.Cys1055Ser variants in BLM have already been reported in BS patients, while the c.572_573delGA;p.Arg191Lysfs 4 variant is novel. Additionally, we present the detailed clinical characteristics of two cases with BS in which we previously identified the biallelic loss‐of‐function variant c.1255_1259delAAGAA;p.Lys419Leufs 5 in RMI1. All BS patients had primary microcephaly, intrauterine growth delay, and short stature, presenting the phenotypic hallmarks of BS. However, skin lesions and upper airway infections were observed only in some of the patients. Overall, patients with pathogenic BLM variants had a more severe BS phenotype compared to patients carrying the pathogenic variants in RMI1, especially in terms of immunodeficiency, which should be considered as one of the most important phenotypic characteristics of BS."],["dc.description.abstract","Phenotypic features of Bloom syndrome differ in severity between patients carrying pathogenic variants in BLM and RMI1. image"],["dc.description.sponsorship","Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Research Group FOR 2800 “Chromosome Instability: Cross‐talk of DNA replication stress and mitotic dysfunction”, SP5 and SPZ"],["dc.description.sponsorship","German Center for Cardiovascular Research (DZHK, partner site Göttingen)"],["dc.description.sponsorship","Germany's Excellence Strategy, Cluster of Excellence \"Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells\" (MBExC; EXC 2067/1‐390729940)"],["dc.identifier.doi","10.1111/cge.14125"],["dc.identifier.pmid","35218564"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/105419"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/455"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-530"],["dc.publisher","Blackwell Publishing Ltd"],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation.eissn","1399-0004"],["dc.relation.issn","0009-9163"],["dc.relation.workinggroup","RG Wollnik"],["dc.rights","This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made."],["dc.rights.uri","http://creativecommons.org/licenses/by-nc-nd/4.0/"],["dc.title","Phenotypic spectrum of BLM‐ and RMI1‐related Bloom syndrome"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.journal","European Journal of Human Genetics"],["dc.contributor.author","Schmidt, Julia"],["dc.contributor.author","Schreiber, Gudrun"],["dc.contributor.author","Altmüller, Janine"],["dc.contributor.author","Thiele, Holger"],["dc.contributor.author","Nürnberg, Peter"],["dc.contributor.author","Li, Yun"],["dc.contributor.author","Kaulfuß, Silke"],["dc.contributor.author","Funke, Rudolf"],["dc.contributor.author","Wilken, Bernd"],["dc.contributor.author","Yigit, Gökhan"],["dc.contributor.author","Wollnik, Bernd"],["dc.date.accessioned","2021-12-01T09:23:16Z"],["dc.date.available","2021-12-01T09:23:16Z"],["dc.date.issued","2021"],["dc.description.abstract","Abstract Variants in transcription factor p63 have been linked to several autosomal dominantly inherited malformation syndromes. These disorders show overlapping phenotypic characteristics with various combinations of the following features: ectodermal dysplasia, split-hand/foot malformation/syndactyly, lacrimal duct obstruction, hypoplastic breasts and/or nipples, ankyloblepharon filiforme adnatum, hypospadias and cleft lip/palate. We describe a family with six individuals presenting with a striking novel phenotype characterized by a furrowed or cleft tongue, a narrow face, reddish hair, freckles and various foot deformities. Whole-exome sequencing (WES) identified a novel heterozygous variant, c.3G>T, in TP63 affecting the translation initiation codon (p.1Met?). Sanger sequencing confirmed dominant inheritance of this unique variant in all six affected family members. In summary, our findings indicate that heterozygous variants in TP63 affecting the first translation initiation codon result in a novel phenotype dominated by a cleft tongue, expanding the complex genotypic and phenotypic spectrum of TP63 -associated disorders."],["dc.identifier.doi","10.1038/s41431-021-00967-x"],["dc.identifier.pii","967"],["dc.identifier.pmid","34629465"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/94604"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/352"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-478"],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation.eissn","1476-5438"],["dc.relation.issn","1018-4813"],["dc.relation.workinggroup","RG Wollnik"],["dc.rights","CC BY 4.0"],["dc.title","Familial cleft tongue caused by a unique translation initiation codon variant in TP63"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","221"],["dc.bibliographiccitation.issue","2"],["dc.bibliographiccitation.journal","The American Journal of Human Genetics"],["dc.bibliographiccitation.lastpage","231"],["dc.bibliographiccitation.volume","103"],["dc.contributor.author","Martin, Carol-Anne"],["dc.contributor.author","Sarlós, Kata"],["dc.contributor.author","Logan, Clare V."],["dc.contributor.author","Thakur, Roshan Singh"],["dc.contributor.author","Parry, David A."],["dc.contributor.author","Bizard, Anna H."],["dc.contributor.author","Leitch, Andrea"],["dc.contributor.author","Cleal, Louise"],["dc.contributor.author","Ali, Nadia Shaukat"],["dc.contributor.author","Al-Owain, Mohammed A."],["dc.contributor.author","Allen, William"],["dc.contributor.author","Altmüller, Janine"],["dc.contributor.author","Aza-Carmona, Miriam"],["dc.contributor.author","Barakat, Bushra A. Y."],["dc.contributor.author","Barraza-García, Jimena"],["dc.contributor.author","Begtrup, Amber"],["dc.contributor.author","Bogliolo, Massimo"],["dc.contributor.author","Cho, Megan T."],["dc.contributor.author","Cruz-Rojo, Jaime"],["dc.contributor.author","Dhahrabi, Hassan Ali Mundi"],["dc.contributor.author","Elcioğlu, Nursel H."],["dc.contributor.author","Gorman, Gráinne S."],["dc.contributor.author","Jobling, Rebekah"],["dc.contributor.author","Kesterton, Ian"],["dc.contributor.author","Kishita, Yoshihito"],["dc.contributor.author","Kohda, Masakazu"],["dc.contributor.author","Le Quesne Stabej, Polona"],["dc.contributor.author","Malallah, Asam Jassim"],["dc.contributor.author","Nürnberg, Peter"],["dc.contributor.author","Ohtake, Akira"],["dc.contributor.author","Okazaki, Yasushi"],["dc.contributor.author","Pujol, Roser"],["dc.contributor.author","Ramirez, Maria José"],["dc.contributor.author","Revah-Politi, Anya"],["dc.contributor.author","Shimura, Masaru"],["dc.contributor.author","Stevens, Paul"],["dc.contributor.author","Taylor, Robert W."],["dc.contributor.author","Turner, Lesley"],["dc.contributor.author","Williams, Hywel"],["dc.contributor.author","Wilson, Carolyn"],["dc.contributor.author","Yigit, Gökhan"],["dc.contributor.author","Zahavich, Laura"],["dc.contributor.author","Alkuraya, Fowzan S."],["dc.contributor.author","Surralles, Jordi"],["dc.contributor.author","Iglesias, Alejandro"],["dc.contributor.author","Murayama, Kei"],["dc.contributor.author","Wollnik, Bernd"],["dc.contributor.author","Dattani, Mehul"],["dc.contributor.author","Heath, Karen E."],["dc.contributor.author","Hickson, Ian D."],["dc.contributor.author","Jackson, Andrew P."],["dc.contributor.authorgroup","GOSgene"],["dc.date.accessioned","2019-02-26T12:12:23Z"],["dc.date.available","2019-02-26T12:12:23Z"],["dc.date.issued","2018"],["dc.description.abstract","Bloom syndrome, caused by biallelic mutations in BLM, is characterized by prenatal-onset growth deficiency, short stature, an erythematous photosensitive malar rash, and increased cancer predisposition. Diagnostically, a hallmark feature is the presence of increased sister chromatid exchanges (SCEs) on cytogenetic testing. Here, we describe biallelic mutations in TOP3A in ten individuals with prenatal-onset growth restriction and microcephaly. TOP3A encodes topoisomerase III alpha (TopIIIα), which binds to BLM as part of the BTRR complex, and promotes dissolution of double Holliday junctions arising during homologous recombination. We also identify a homozygous truncating variant in RMI1, which encodes another component of the BTRR complex, in two individuals with microcephalic dwarfism. The TOP3A mutations substantially reduce cellular levels of TopIIIα, and consequently subjects’ cells demonstrate elevated rates of SCE. Unresolved DNA recombination and/or replication intermediates persist into mitosis, leading to chromosome segregation defects and genome instability that most likely explain the growth restriction seen in these subjects and in Bloom syndrome. Clinical features of mitochondrial dysfunction are evident in several individuals with biallelic TOP3A mutations, consistent with the recently reported additional function of TopIIIα in mitochondrial DNA decatenation. In summary, our findings establish TOP3A mutations as an additional cause of prenatal-onset short stature with increased cytogenetic SCEs and implicate the decatenation activity of the BTRR complex in their pathogenesis."],["dc.identifier.doi","10.1016/j.ajhg.2018.07.001"],["dc.identifier.pmid","30057030"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/57617"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/218"],["dc.language.iso","en"],["dc.notes.status","fcwi"],["dc.relation","SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz"],["dc.relation","SFB 1002 | D02: Neue Mechanismen der genomischen Instabilität bei Herzinsuffizienz"],["dc.relation.issn","0002-9297"],["dc.relation.workinggroup","RG Wollnik"],["dc.rights","CC BY-NC-ND 4.0"],["dc.title","Mutations in TOP3A Cause a Bloom Syndrome-like Disorder"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]