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dc.contributor.authorMartens, Helge
dc.contributor.authorHennies, Imke
dc.contributor.authorGetwan, Maike
dc.contributor.authorChristians, Anne
dc.contributor.authorWeiss, Anna-Carina
dc.contributor.authorBrand, Frank
dc.contributor.authorGjerstad, Ann Christin
dc.contributor.authorChristians, Arne
dc.contributor.authorGucev, Zoran
dc.contributor.authorGeffers, Robert
dc.contributor.authorSeeman, Tomáš
dc.contributor.authorKispert, Andreas
dc.contributor.authorTasic, Velibor
dc.contributor.authorBjerre, Anna
dc.contributor.authorLienkamp, Soeren S
dc.contributor.authorHaffner, Dieter
dc.contributor.authorWeber, Ruthild G
dc.date.accessioned2020-10-05T14:17:57Z
dc.date.available2020-10-05T14:17:57Z
dc.date.issued2020-07-31
dc.identifier.citationEur J Hum Genet. 2020 Jul 31. doi: 10.1038/s41431-020-0678-9. Epub ahead of print.en_US
dc.identifier.pmid32737436
dc.identifier.doi10.1038/s41431-020-0678-9
dc.identifier.urihttp://hdl.handle.net/10033/622498
dc.description.abstractAlthough over 50 genes are known to cause renal malformation if mutated, the underlying genetic basis, most easily identified in syndromic cases, remains unsolved in most patients. In search of novel causative genes, whole-exome sequencing in a patient with renal, i.e., crossed fused renal ectopia, and extrarenal, i.e., skeletal, eye, and ear, malformations yielded a rare heterozygous variant in the GDF6 gene encoding growth differentiation factor 6, a member of the BMP family of ligands. Previously, GDF6 variants were reported to cause pleiotropic defects including skeletal, e.g., vertebral, carpal, tarsal fusions, and ocular, e.g., microphthalmia and coloboma, phenotypes. To assess the role of GDF6 in the pathogenesis of renal malformation, we performed targeted sequencing in 193 further patients identifying rare GDF6 variants in two cases with kidney hypodysplasia and extrarenal manifestations. During development, gdf6 was expressed in the pronephric tubule of Xenopus laevis, and Gdf6 expression was observed in the ureteric tree of the murine kidney by RNA in situ hybridization. CRISPR/Cas9-derived knockout of Gdf6 attenuated migration of murine IMCD3 cells, an effect rescued by expression of wild-type but not mutant GDF6, indicating affected variant function regarding a fundamental developmental process. Knockdown of gdf6 in Xenopus laevis resulted in impaired pronephros development. Altogether, we identified rare heterozygous GDF6 variants in 1.6% of all renal anomaly patients and 5.4% of renal anomaly patients additionally manifesting skeletal, ocular, or auricular abnormalities, adding renal hypodysplasia and fusion to the phenotype spectrum of GDF6 variant carriers and suggesting an involvement of GDF6 in nephrogenesis.en_US
dc.language.isoenen_US
dc.publisherSpringer Natureen_US
dc.rightsAttribution-NonCommercial-ShareAlike 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.titleRare heterozygous GDF6 variants in patients with renal anomalies.en_US
dc.typeArticleen_US
dc.identifier.eissn1476-5438
dc.contributor.departmentHZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.en_US
dc.identifier.journalEuropean journal of human genetics : EJHGen_US
refterms.dateFOA2020-10-05T14:17:58Z
dc.source.journaltitleEuropean journal of human genetics : EJHG
dc.source.countryEngland


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