4.7 Article

Mutations in PRDM15 Are a Novel Cause of Galloway-Mowat Syndrome

Journal

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
Volume 32, Issue 3, Pages 580-596

Publisher

AMER SOC NEPHROLOGY
DOI: 10.1681/ASN.2020040490

Keywords

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Funding

  1. National Institutes of Health [T32DK007726, DK076683]
  2. German Ministry of Education and Research (GeNeRARe) [01GM1519A]
  3. Eliteprogramm of the Baden-Wuerttemberg Stiftung
  4. Care for Rare Foundation
  5. Eva Luise and Horst Kohler Foundation
  6. Else Kroner Fresenius Foundation [2018_A78]
  7. Volkswagen Foundation
  8. National Medical Research Council, NMRC, Singapore [NMRC/OFIRG/0032/2017]
  9. National Research Foundation, NRF, Singapore [NRF-CRP17-2017-06]
  10. National Institutes of Health at Boston Children's Hospital [T32-DK007726-33]
  11. German Research Foundation [VK 403877094, Jo 1324/1-1, 404527522, VE 969]
  12. National Center for Scientific Research/French National Institute of Health and Medical Research ATIP-AVENIR start-up grant
  13. F32 Ruth L. Kirschstein National Research Service Award [DK122766]
  14. KRESCENT Program, a national kidney research training partnership of the Kidney Foundation of Canada
  15. Canadian Society of Nephrology
  16. Canadian Institutes of Health Research
  17. Harvard Stem Cell Institute
  18. American Society of Nephrology Lipps Research Program 2018 Polycystic Kidney Disease Foundation Jared J. Grantham Research Fellowship
  19. Yale Center for Mendelian Genomics [U54HG006504]
  20. National Human Genome Research Institute
  21. National Eye Institute
  22. National Heart, Lung and Blood Institute [UM1 HG008900]

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Variants in the transcriptional regulator PRDM15 are found to cause proteinuric kidney disease in six families, with four of them displaying additional features of a GAMOS-like syndrome. All variants destabilize the PRDM15 protein, with the ZNF variant also interfering with transcriptional activation. Knockdown of Prdm15 in Xenopus embryos disrupts pronephric development, and CRISPR-mediated knockout of PRDM15 in human podocytes leads to dysregulation of renal developmental genes.
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.

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