Yigit, Gökhan

[["dc.bibliographiccitation.artnumber","4091"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Scientific Reports"],["dc.bibliographiccitation.volume","12"],["dc.contributor.author","Shomroni, Orr"],["dc.contributor.author","Sitte, Maren"],["dc.contributor.author","Schmidt, Julia"],["dc.contributor.author","Parbin, Sabnam"],["dc.contributor.author","Ludewig, Fabian"],["dc.contributor.author","Yigit, Gökhan"],["dc.contributor.author","Zelarayan, Laura Cecilia"],["dc.contributor.author","Streckfuss-Bömeke, Katrin"],["dc.contributor.author","Wollnik, Bernd"],["dc.contributor.author","Salinas, Gabriella"],["dc.date.accessioned","2022-04-01T10:01:43Z"],["dc.date.available","2022-04-01T10:01:43Z"],["dc.date.issued","2022"],["dc.description.abstract","Single cell multi-omics analysis has the potential to yield a comprehensive understanding of the cellular events that underlie the basis of human diseases. The cardinal feature to access this information is the technology used for single-cell isolation, barcoding, and sequencing. Most currently used single-cell RNA-sequencing platforms have limitations in several areas including cell selection, documentation and library chemistry. In this study, we describe a novel high-throughput, full-length, single-cell RNA-sequencing approach that combines the CellenONE isolation and sorting system with the ICELL8 processing instrument. This method offers substantial improvements in single cell selection, documentation and capturing rate. Moreover, it allows the use of flexible chemistry for library preparations and the analysis of living or fixed cells, whole cells independent of sizing and morphology, as well as of nuclei. We applied this method to dermal fibroblasts derived from six patients with different segmental progeria syndromes and defined phenotype associated pathway signatures with variant associated expression modifiers. These results validate the applicability of our method to highlight genotype-expression relationships for molecular phenotyping of individual cells derived from human patients."],["dc.description.sponsorship","Georg-August-Universität Göttingen"],["dc.description.sponsorship","Open-Access-Publikationsfonds 2022"],["dc.identifier.doi","10.1038/s41598-022-07874-1"],["dc.identifier.pii","7874"],["dc.identifier.pmid","35260714"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/105735"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/460"],["dc.identifier.url","https://sfb1002.med.uni-goettingen.de/production/literature/publications/424"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-530"],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation","SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz"],["dc.relation.eissn","2045-2322"],["dc.relation.workinggroup","RG Wollnik"],["dc.relation.workinggroup","RG Zelarayán-Behrend (Developmental Pharmacology)"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","A novel single-cell RNA-sequencing approach and its applicability connecting genotype to phenotype in ageing disease"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["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","341"],["dc.bibliographiccitation.issue","2"],["dc.bibliographiccitation.journal","Genetics in Medicine"],["dc.bibliographiccitation.lastpage","351"],["dc.bibliographiccitation.volume","23"],["dc.contributor.author","Schröder, Simone"],["dc.contributor.author","Li, Yun"],["dc.contributor.author","Yigit, Gökhan"],["dc.contributor.author","Altmüller, Janine"],["dc.contributor.author","Bader, Ingrid"],["dc.contributor.author","Bevot, Andrea"],["dc.contributor.author","Biskup, Saskia"],["dc.contributor.author","Dreha-Kulaczewski, Steffi"],["dc.contributor.author","Christoph Korenke, G."],["dc.contributor.author","Kottke, Raimund"],["dc.contributor.author","Mayr, Johannes A."],["dc.contributor.author","Preisel, Martin"],["dc.contributor.author","Toelle, Sandra P."],["dc.contributor.author","Wente-Schulz, Sarah"],["dc.contributor.author","Wortmann, Saskia B."],["dc.contributor.author","Hahn, Heidi"],["dc.contributor.author","Boltshauser, Eugen"],["dc.contributor.author","Uhmann, Anja"],["dc.contributor.author","Wollnik, Bernd"],["dc.contributor.author","Brockmann, Knut"],["dc.date.accessioned","2021-04-14T08:31:50Z"],["dc.date.available","2021-04-14T08:31:50Z"],["dc.date.issued","2020"],["dc.description.abstract","Purpose\r\n\r\nThis study aimed to delineate the genetic basis of congenital ocular motor apraxia (COMA) in patients not otherwise classifiable.\r\nMethods\r\n\r\nWe compiled clinical and neuroimaging data of individuals from six unrelated families with distinct clinical features of COMA who do not share common diagnostic characteristics of Joubert syndrome or other known genetic conditions associated with COMA. We used exome sequencing to identify pathogenic variants and functional studies in patient-derived fibroblasts.\r\nResults\r\n\r\nIn 15 individuals, we detected familial as well as de novo heterozygous truncating causative variants in the Suppressor of Fused (SUFU) gene, a negative regulator of the Hedgehog (HH) signaling pathway. Functional studies showed no differences in cilia occurrence, morphology, or localization of ciliary proteins, such as smoothened. However, analysis of expression of HH signaling target genes detected a significant increase in the general signaling activity in COMA patient–derived fibroblasts compared with control cells. We observed higher basal HH signaling activity resulting in increased basal expression levels of GLI1, GLI2, GLI3, and Patched1. Neuroimaging revealed subtle cerebellar changes, but no full-blown molar tooth sign.\r\nConclusion\r\n\r\nTaken together, our data imply that the clinical phenotype associated with heterozygous truncating germline variants in SUFU is a forme fruste of Joubert syndrome."],["dc.identifier.doi","10.1038/s41436-020-00979-w"],["dc.identifier.pmid","33024317"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/83726"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/80"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-399"],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation.eissn","1530-0366"],["dc.relation.issn","1098-3600"],["dc.relation.workinggroup","RG Wollnik"],["dc.rights","CC BY 4.0"],["dc.title","Heterozygous truncating variants in SUFU cause congenital ocular motor apraxia"],["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","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.firstpage","2971"],["dc.bibliographiccitation.issue","12"],["dc.bibliographiccitation.journal","American Journal of Medical Genetics Part A"],["dc.bibliographiccitation.lastpage","2975"],["dc.bibliographiccitation.volume","182"],["dc.contributor.author","Schröder, Simone"],["dc.contributor.author","Wieland, Britta"],["dc.contributor.author","Ohlenbusch, Andreas"],["dc.contributor.author","Yigit, Gökhan"],["dc.contributor.author","Altmüller, Janine"],["dc.contributor.author","Boltshauser, Eugen"],["dc.contributor.author","Dörk, Thilo"],["dc.contributor.author","Brockmann, Knut"],["dc.date.accessioned","2021-04-14T08:23:43Z"],["dc.date.available","2021-04-14T08:23:43Z"],["dc.date.issued","2020"],["dc.description.abstract","Abstract Mild clinical phenotypes of ataxia‐telangiectasia (variant A‐T) are associated with biallelic ATM variants resulting in residual function of the ATM kinase. At least one regulatory, missense, or leaky splice site mutation resulting in expression of ATM with low level kinase activity was identified in subjects with variant A‐T. Studies on the pathogenicity of the germline splicing ATM variant c.1066‐6T\\u0026gt;G have provided conflicting results. Using whole‐exome sequencing, we identified two splice site ATM variants, c.1066‐6T\\u0026gt;G; [p.?], and c.2250G\\u0026gt;A, [p.Ile709_Lys750del], in a compound heterozygous state in a 27‐year‐old woman who had been diagnosed as having congenital ocular motor apraxia type Cogan in her childhood. Reappraisal of her clinical phenotype revealed consistency with variant A‐T. Functional analyses showed reduced expression of ATM protein and residual activity of the ATM kinase at a level consistent with variant A‐T. Our results provide evidence for pathogenicity of the leaky ATM splice site variant c.1066‐6T\\u0026gt;G."],["dc.description.sponsorship","Claudia von Schilling Foundation for Breast Cancer Research"],["dc.description.sponsorship","Niedersächsische Ministerium für Wissenschaft und Kultur http://dx.doi.org/10.13039/501100010570"],["dc.identifier.doi","10.1002/ajmg.a.61870"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/81021"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-399"],["dc.publisher","John Wiley \\u0026 Sons, Inc."],["dc.relation.eissn","1552-4833"],["dc.relation.issn","1552-4825"],["dc.rights","This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited."],["dc.title","Evidence of pathogenicity for the leaky splice variant c. 1066‐6T >G in ATM"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","e330"],["dc.bibliographiccitation.issue","3"],["dc.bibliographiccitation.journal","Neurology Genetics"],["dc.bibliographiccitation.volume","5"],["dc.contributor.author","Nagy, Vanja"],["dc.contributor.author","Hollstein, Ronja"],["dc.contributor.author","Pai, Tsung-Pin"],["dc.contributor.author","Herde, Michel K."],["dc.contributor.author","Buphamalai, Pisanu"],["dc.contributor.author","Moeseneder, Paul"],["dc.contributor.author","Lenartowicz, Ewelina"],["dc.contributor.author","Kavirayani, Anoop"],["dc.contributor.author","Korenke, Georg Christoph"],["dc.contributor.author","Kozieradzki, Ivona"],["dc.contributor.author","Nitsch, Roberto"],["dc.contributor.author","Cicvaric, Ana"],["dc.contributor.author","Monje Quiroga, Francisco J."],["dc.contributor.author","Deardorff, Matthew A."],["dc.contributor.author","Bedoukian, Emma C."],["dc.contributor.author","Li, Yun"],["dc.contributor.author","Yigit, Gökhan"],["dc.contributor.author","Menche, Jörg"],["dc.contributor.author","Perçin, E. Ferda"],["dc.contributor.author","Wollnik, Bernd"],["dc.contributor.author","Henneberger, Christian"],["dc.contributor.author","Kaiser, Frank J."],["dc.contributor.author","Penninger, Josef M."],["dc.date.accessioned","2020-12-10T18:41:40Z"],["dc.date.available","2020-12-10T18:41:40Z"],["dc.date.issued","2019"],["dc.identifier.doi","10.1212/NXG.0000000000000330"],["dc.identifier.eissn","2376-7839"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/16714"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/77644"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-354"],["dc.notes.intern","Merged from goescholar"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","HACE1 deficiency leads to structural and functional neurodevelopmental defects"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["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.firstpage","391"],["dc.bibliographiccitation.issue","3"],["dc.bibliographiccitation.journal","The American Journal of Human Genetics"],["dc.bibliographiccitation.lastpage","403"],["dc.bibliographiccitation.volume","101"],["dc.contributor.author","Windpassinger, Christian"],["dc.contributor.author","Piard, Juliette"],["dc.contributor.author","Bonnard, Carine"],["dc.contributor.author","Alfadhel, Majid"],["dc.contributor.author","Lim, Shuhui"],["dc.contributor.author","Bisteau, Xavier"],["dc.contributor.author","Blouin, Stéphane"],["dc.contributor.author","Ali, Nur’Ain B."],["dc.contributor.author","Ng, Alvin Yu Jin"],["dc.contributor.author","Lu, Hao"],["dc.contributor.author","Tohari, Sumanty"],["dc.contributor.author","Talib, S. Zakiah A."],["dc.contributor.author","van Hul, Noémi"],["dc.contributor.author","Caldez, Matias J."],["dc.contributor.author","Van Maldergem, Lionel"],["dc.contributor.author","Yigit, Gökhan"],["dc.contributor.author","Kayserili, Hülya"],["dc.contributor.author","Youssef, Sameh A."],["dc.contributor.author","Coppola, Vincenzo"],["dc.contributor.author","de Bruin, Alain"],["dc.contributor.author","Tessarollo, Lino"],["dc.contributor.author","Choi, Hyungwon"],["dc.contributor.author","Rupp, Verena"],["dc.contributor.author","Roetzer, Katharina"],["dc.contributor.author","Roschger, Paul"],["dc.contributor.author","Klaushofer, Klaus"],["dc.contributor.author","Altmüller, Janine"],["dc.contributor.author","Roy, Sudipto"],["dc.contributor.author","Venkatesh, Byrappa"],["dc.contributor.author","Ganger, Rudolf"],["dc.contributor.author","Grill, Franz"],["dc.contributor.author","Ben Chehida, Farid"],["dc.contributor.author","Wollnik, Bernd"],["dc.contributor.author","Altunoglu, Umut"],["dc.contributor.author","Al Kaissi, Ali"],["dc.contributor.author","Reversade, Bruno"],["dc.contributor.author","Kaldis, Philipp"],["dc.date.accessioned","2018-04-23T11:49:09Z"],["dc.date.available","2018-04-23T11:49:09Z"],["dc.date.issued","2017"],["dc.description.abstract","In five separate families, we identified nine individuals affected by a previously unidentified syndrome characterized by growth retardation, spine malformation, facial dysmorphisms, and developmental delays. Using homozygosity mapping, array CGH, and exome sequencing, we uncovered bi-allelic loss-of-function CDK10 mutations segregating with this disease. CDK10 is a protein kinase that partners with cyclin M to phosphorylate substrates such as ETS2 and PKN2 in order to modulate cellular growth. To validate and model the pathogenicity of these CDK10 germline mutations, we generated conditional-knockout mice. Homozygous Cdk10-knockout mice died postnatally with severe growth retardation, skeletal defects, and kidney and lung abnormalities, symptoms that partly resemble the disease’s effect in humans. Fibroblasts derived from affected individuals and Cdk10-knockout mouse embryonic fibroblasts (MEFs) proliferated normally; however, Cdk10-knockout MEFs developed longer cilia. Comparative transcriptomic analysis of mutant and wild-type mouse organs revealed lipid metabolic changes consistent with growth impairment and altered ciliogenesis in the absence of CDK10. Our results document the CDK10 loss-of-function phenotype and point to a function for CDK10 in transducing signals received at the primary cilia to sustain embryonic and postnatal development."],["dc.identifier.doi","10.1016/j.ajhg.2017.08.003"],["dc.identifier.gro","3142500"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/16385"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/13653"],["dc.language.iso","en"],["dc.notes.intern","lifescience updates Crossref Import"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","final"],["dc.relation.issn","0002-9297"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","CDK10 Mutations in Humans and Mice Cause Severe Growth Retardation, Spine Malformations, and Developmental Delays"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dc.type.peerReviewed","no"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]