Mutations in WDR4 as a new cause of Galloway–Mowat syndrome

Abstract

Galloway-Mowat syndrome (GAMOS) is a phenotypically heterogeneous disorder characterized by neurodevelopmental defects combined with renal-glomerular disease, manifesting with proteinuria. To identify additional monogenic disease causes, we here performed whole exome sequencing (WES), linkage analysis, and homozygosity mapping in three affected siblings of an Indian family with GAMOS. Applying established criteria for variant filtering, we identify a novel homozygous splice site mutation in the gene WDR4 as the likely disease-causing mutation in this family. In line with previous reports, we observe growth deficiency, microcephaly, developmental delay, and intellectual disability as phenotypic features resulting from WDR4 mutations. However, the newly identified allele additionally gives rise to proteinuria and nephrotic syndrome, a phenotype that was never reported in patients with WDR4 mutations. Our data thus expand the phenotypic spectrum of WDR4 mutations by demonstrating that, depending on the specific mutated allele, a renal phenotype may be present. This finding suggests that GAMOS may occupy a phenotypic spectrum with other microcephalic diseases. Furthermore, WDR4 is an additional example of a gene that encodes a tRNA modifying enzyme and gives rise to GAMOS, if mutated. Our findings thereby support the recent observation that, like neurons, podocytes of the renal glomerulus are particularly vulnerable to cellular defects resulting from altered tRNA modifications.

Hypomodified tRNA in evolutionarily distant yeasts can trigger rapid tRNA decay to activate the general amino acid control response, but with different consequences

“…pombe , we speculate that the RTD pathway is conserved throughout eukaryotes. The existence of a mammalian RTD pathway could explain the reduced levels of specific tRNA species in mouse strains lacking m 5 C in their tRNAs [ 33 , 87 ] and in mouse embryonic stem cells lacking m 7 G in their tRNAs [ 46 ], and might explain other phenotypes associated with mutations in METTL1 or WDR4 [ 29 , 30 , 46 , 88 ].…”

Defects in t6A tRNA modification due to GON7 and YRDC mutations lead to Galloway-Mowat syndrome

“…An increasing number of mutations are being identified in genes encoding tRNA-modifying enzymes that are linked to human neurodevelopmental disorders. Very recently, mutations in WDR4 , initially described to cause a distinct form of microcephalic primordial dwarfism and brain malformations 30,31 , have been identified in individuals with GAMOS 14 . WDR4 is a component of the METTL1/WDR4 holoenzyme, an N 7 -methylguanosine (m 7 G) methyltransferase that is responsible for the highly conserved m 7 G modification on a specific subset of tRNAs 32,33 .…”

Expanding the phenotype of biallelic loss‐of‐function variants in the NSUN2 gene: Description of four individuals with juvenile cataract, chronic nephritis, or brain anomaly as novel complications

“…Hence, juvenile cataract shown in the present cases may be due to the NSUN2 pathogenic variants. As for the renal dysfunction, it is also reported as one of the complications associated with another tRNA modification-related disorder, like Galloway-Mowat syndrome caused by WDR4 dysfunction (Braun et al, 2018). Given that NSUN2 is an essential enzyme to catalyze the methylation of the tRNA precursor, which is crucial for translation, and the NSUN2 mRNA is reported to be ubiquitously expressed, we postulate that NSUN2 deficiency can cause renal abnormalities (Abbasi-Moheb et al, 2012).…”