RT Journal Article SR Electronic T1 Mutations in PRDM15 Are a Novel Cause of Galloway-Mowat Syndrome JF Journal of the American Society of Nephrology JO J. Am. Soc. Nephrol. FD American Society of Nephrology SP ASN.2020040490 DO 10.1681/ASN.2020040490 A1 Mann, Nina A1 Mzoughi, Slim A1 Schneider, Ronen A1 Kühl, Susanne J. A1 Schanze, Denny A1 Klämbt, Verena A1 Lovric, Svjetlana A1 Mao, Youying A1 Shi, Shasha A1 Tan, Weizhen A1 Kühl, Michael A1 Onuchic-Whitford, Ana C. A1 Treimer, Ernestine A1 Kitzler, Thomas M. A1 Kause, Franziska A1 Schumann, Sven A1 Nakayama, Makiko A1 Buerger, Florian A1 Shril, Shirlee A1 van der Ven, Amelie T. A1 Majmundar, Amar J. A1 Holton, Kristina Marie A1 Kolb, Amy A1 Braun, Daniela A. A1 Rao, Jia A1 Jobst-Schwan, Tilman A1 Mildenberger, Eva A1 Lennert, Thomas A1 Kuechler, Alma A1 Wieczorek, Dagmar A1 Gross, Oliver A1 Ermisch-Omran, Beate A1 Werberger, Anja A1 Skalej, Martin A1 Janecke, Andreas R. A1 Soliman, Neveen A. A1 Mane, Shrikant M. A1 Lifton, Richard P. A1 Kadlec, Jan A1 Guccione, Ernesto A1 Schmeisser, Michael J. A1 Zenker, Martin A1 Hildebrandt, Friedhelm YR 2021 UL http://jasn.asnjournals.org/content/early/2021/02/15/ASN.2020040490.abstract AB Proteinuric kidney disease is a leading cause of ESKD in children. It is part of Galloway-Mowat syndrome, a rare condition that includes a severe form of progressive nephropathy and prominent central nervous system features. The most common renal manifestation is steroid-resistant nephrotic syndrome. Mutations in the transcriptional regulator PRDM15 are a novel monogenic cause of both isolated early-onset nephrotic syndrome and Galloway-Mowat syndrome. Identifying variants in PRDM15 in these disorders provides insight into the molecular pathogenesis of nephrotic syndrome and implicates the gene as an important regulator of renal development.Background Galloway-Mowat syndrome (GAMOS) is characterized by neurodevelopmental defects and a progressive nephropathy, which typically manifests as steroid-resistant nephrotic syndrome. The prognosis of GAMOS is poor, and the majority of children progress to renal failure. The discovery of monogenic causes of GAMOS has uncovered molecular pathways involved in the pathogenesis of disease.Methods Homozygosity mapping, whole-exome sequencing, and linkage analysis were used to identify mutations in four families with a GAMOS-like phenotype, and high-throughput PCR technology was applied to 91 individuals with GAMOS and 816 individuals with isolated nephrotic syndrome. In vitro and in vivo studies determined the functional significance of the mutations identified.Results Three biallelic variants of the transcriptional regulator PRDM15 were detected in six families with proteinuric kidney disease. Four families with a variant in the protein’s zinc-finger (ZNF) domain have additional GAMOS-like features, including brain anomalies, cardiac defects, and skeletal defects. All variants destabilize the PRDM15 protein, and the ZNF variant additionally interferes with transcriptional activation. Morpholino oligonucleotide-mediated knockdown of Prdm15 in Xenopus embryos disrupted pronephric development. Human wild-type PRDM15 RNA rescued the disruption, but the three PRDM15 variants did not. Finally, CRISPR-mediated knockout of PRDM15 in human podocytes led to dysregulation of several renal developmental genes.Conclusions Variants in PRDM15 can cause either isolated nephrotic syndrome or a GAMOS-type syndrome on an allelic basis. PRDM15 regulates multiple developmental kidney genes, and is likely to play an essential role in renal development in humans.