Mutations in PRDM15 Are a Novel Cause of Galloway-Mowat Syndrome
Authors: Mann Nina , Mzoughi Slim , Schneider Ronen , Kühl Susanne J. , Schanze Denny , Klämbt Verena , Lovric Svjetlana , Mao Youying , Shi Shasha , Tan Weizhen , Kühl Michael , Onuchic-Whitford Ana C. , Treimer Ernestine , Kitzler Thomas M. , Kause Franziska , Schumann Sven , Nakayama Makiko , Buerger Florian , Shril Shirlee , van der Ven Amelie T. , Majmundar Amar J. , Holton Kristina Marie , Kolb Amy , Braun Daniela A. , Rao Jia , Jobst-Schwan Tilman , Mildenberger Eva , Lennert Thomas , Kuechler Alma , Wieczorek Dagmar , Gross Oliver , Ermisch-Omran Beate , Werberger Anja , Skalej Martin , Janecke Andreas R. , Soliman Neveen A. , Mane Shrikant M. , Lifton Richard P. , Kadlec Jan , Guccione Ernesto , Schmeisser Michael J. , Zenker Martin , Hildebrandt Friedhelm 
Published: February 2021

Significance Statement
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.