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J Am Soc Nephrol 2021 Mar 01;323:580-596. doi: 10.1681/ASN.2020040490.
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Mutations in PRDM15 Are a Novel Cause of Galloway-Mowat Syndrome.

Mann N , Mzoughi S , Schneider R , Kühl SJ , Schanze D , Klämbt V , Lovric S , Mao Y , Shi S , Tan W , Kühl M , Onuchic-Whitford AC , Treimer E , Kitzler TM , Kause F , Schumann S , Nakayama M , Buerger F , Shril S , van der Ven AT , Majmundar AJ , Holton KM , Kolb A , Braun DA , Rao J , Jobst-Schwan T , Mildenberger E , Lennert T , Kuechler A , Wieczorek D , Gross O , Ermisch-Omran B , Werberger A , Skalej M , Janecke AR , Soliman NA , Mane SM , Lifton RP , Kadlec J , Guccione E , Schmeisser MJ , Zenker M , Hildebrandt F .

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.

PubMed ID: 33593823
PMC ID: PMC7920168
Article link: J Am Soc Nephrol
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: foxc1 fxyd2 lhx1 prdm15 slc12a1 slc5a1.2 wt1
Morpholinos: prdm15 MO1

Disease Ontology terms: Galloway-Mowat syndrome 1 [+]
Phenotypes: Xla Wt + prdm15 MO + GFP (Fig 3 EFGHIJKL) [+]

Article Images: [+] show captions
References [+] :
Abouelhoda, Clinical genomics can facilitate countrywide estimation of autosomal recessive disease burden. 2016, Pubmed