Rare heterozygous GDF6 variants in patients with renal anomalies.
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Authors
Martens, HelgeHennies, Imke
Getwan, Maike
Christians, Anne
Weiss, Anna-Carina
Brand, Frank
Gjerstad, Ann Christin
Christians, Arne
Gucev, Zoran
Geffers, Robert
Seeman, Tomáš
Kispert, Andreas
Tasic, Velibor
Bjerre, Anna
Lienkamp, Soeren S
Haffner, Dieter
Weber, Ruthild G
Issue Date
2020-07-31
Metadata
Show full item recordAbstract
Although 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.Citation
Eur J Hum Genet. 2020 Jul 31. doi: 10.1038/s41431-020-0678-9. Epub ahead of print.Affiliation
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.Publisher
Springer NaturePubMed ID
32737436Type
ArticleLanguage
enEISSN
1476-5438ae974a485f413a2113503eed53cd6c53
10.1038/s41431-020-0678-9
Scopus Count
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