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

Abstract

BackgroundGalloway-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.MethodsHomozygosity 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.ResultsThree 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.ConclusionsVariants 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.

Novel TP53RK variants cause varied clinical features of Galloway–Mowat syndrome without nephrotic syndrome in three unrelated Chinese patients

“…These genes are located in autosomes, except for the LAGE3 gene with X-linked inheritance ( Rosti et al, 2017 ; Braun et al, 2018 ; Fujita et al, 2018 ; Arrondel et al, 2019 ; Domingo-Gallego et al, 2019 ). A recent study showed that PRDM15 gene variants can cause GAMOS ( Mann et al, 2021 ). Galloway–Mowat syndrome-4 (OMIM, #617730) is a type of GAMOS caused by the TP53-regulating kinase ( TP53RK ) homozygous or compound heterozygous variant.…”

Genomic, Proteomic, and Phenotypic Spectrum of Novel O-Sialoglycoprotein Endopeptidase Variant in Four Affected Individuals With Galloway-Mowat Syndrome

“…In 2014, Colin et al first identified that WDR73 variants caused GAMOS in two unrelated families ( Colin et al, 2014 ). During the last 5 years, several studies have described different variants in WDR73 ( Colin et al, 2014 ; Ben-Omran et al, 2015 ; Jinks et al, 2015 ; Vodopiutz et al, 2015 ; Rosti et al, 2016 ; Jiang et al, 2017 ), NUP107 ( Rosti et al, 2017 ), WHAMM ( Mathiowetz et al, 2017 ), and PRDM15 ( Mann et al, 2021 ) as a causal agent for GAMOS.…”

The duality of PRDM proteins: epigenetic and structural perspectives

“…This role seems to be bypassed in vivo , at least partially, as PRDM15KO mice implant normally and die at mid‐gestation due to growth delay and forebrain malformations reminiscent of holoprosencephaly (HPE) and microcephaly [106]. Indeed, loss‐of‐function mutations affecting the ZNF domains of PRDM15 have been recently reported in patients with a syndromic from of HPE [106,107]. One particular mutation (C844Y) in ZNF15 appears to abolish PRDM15 binding to its target genes, many of which are important for anterior/posterior patterning and forebrain development, and its ability to regulate their expression [106].…”