Mutations in PRDM15 Are a Novel Cause of Galloway-Mowat Syndrome
- 16 February 2021
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Journal of the American Society of Nephrology
- Vol. 32 (3), 580-596
- https://doi.org/10.1681/asn.2020040490
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. 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.Keywords
Funding Information
- National Institutes of Health (DK076683)
- German Ministry of Education and Research
- Baden-Wuerttemberg Stiftung
- Care for Rare foundation
- Eva Luise and Horst Köhler Foundation
- Else Kröner Fresenius Foundation (2018_A78)
- Volkswagen Foundation
- German Ministry of Education and Research (01GM1519A)
- National Medical Research Council (NMRC/OFIRG/0032/2017)
- National Research Foundation (NRF-CRP17-2017-06)
- National Institutes of Health (T32-DK007726-33,)
- German Research Foundation (VK 403877094, Jo 1324/1-1)
- CNRS/INSERM
- Ruth L. Kirschstein National Research (DK122766)
- German Research Foundation (404527522)
- Kidney Foundation of Canada
- Canadian Society of Nephrology
- Canadian Institutes of Health Research
- German Research Foundation (VE 969 -7)
- National Institutes of Health (T32DK-007726)
- Harvard Stem Cell Institute
- American Society of Nephrology
- Yale Center for Mendelian Genomics (U54HG006504)
- Broad Institute of MIT
- Harvard Center for Mendelian Genomics
- National Human Genome Research Institute
- National Eye Institute
- National Heart, Lung and Blood Institute (UM1 HG008900)
This publication has 52 references indexed in Scilit:
- STAR: ultrafast universal RNA-seq alignerBioinformatics, 2012
- Differential expression analysis of multifactor RNA-Seq experiments with respect to biological variationNucleic Acids Research, 2012
- Wt1a, Foxc1a, and the Notch mediator Rbpj physically interact and regulate the formation of podocytes in zebrafishDevelopmental Biology, 2011
- Candidate exome capture identifies mutation of SDCCAG8 as the cause of a retinal-renal ciliopathyNature Genetics, 2010
- Gene ontology analysis for RNA-seq: accounting for selection biasGenome Biology, 2010
- Semaphorin3a regulates endothelial cell number and podocyte differentiation during glomerular developmentDevelopment, 2009
- edgeR: a Bioconductor package for differential expression analysis of digital gene expression dataBioinformatics, 2009
- Organization of the pronephric kidney revealed by large-scale gene expression mappingGenome Biology, 2008
- Family expansion and gene rearrangements contributed to the functional specialization of PRDM genes in vertebratesBMC Evolutionary Biology, 2007
- Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1Nature Genetics, 1997