@article {204953, title = {Mutations in Are a Novel Cause of Galloway-Mowat Syndrome.}, journal = {Journal of the American Society of Nephrology : JASN}, volume = {32}, year = {2021}, pages = {580-596}, abstract = {

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. and studies determined the functional significance of the mutations identified.

RESULTS: Three biallelic variants of the transcriptional regulator were detected in six families with proteinuric kidney disease. Four families with a variant in the protein{\textquoteright}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 embryos disrupted pronephric development. Human wild-type RNA rescued the disruption, but the three variants did not. Finally, CRISPR-mediated knockout of in human podocytes led to dysregulation of several renal developmental genes.

CONCLUSIONS: Variants in 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.

}, author = {Mann, Nina and Mzoughi, Slim and Schneider, Ronen and K{\"u}hl, Susanne J and Schanze, Denny and Kl{\"a}mbt, Verena and Lovric, Svjetlana and Mao, Youying and Shi, Shasha and Weizhen Tan and K{\"u}hl, Michael and Onuchic-Whitford, Ana C and Treimer, Ernestine and Kitzler, Thomas M and Kause, Franziska and Schumann, Sven and Nakayama, Makiko and Buerger, Florian and Shirlee Shril and van der Ven, Amelie T and Majmundar, Amar J and Holton, Kristina Marie and Kolb, Amy and Braun, Daniela A and Rao, Jia and Jobst-Schwan, Tilman and Mildenberger, Eva and Lennert, Thomas and Kuechler, Alma and Wieczorek, Dagmar and Gross, Oliver and Ermisch-Omran, Beate and Werberger, Anja and Skalej, Martin and Janecke, Andreas R and Neveen A Soliman and Mane, Shrikant M and Richard P Lifton and Kadlec, Jan and Guccione, Ernesto and Schmeisser, Michael J and Martin Zenker and Friedhelm Hildebrandt} }