Abstract
Several studies have reported WDR73 mutations to be causative of Galloway–Mowat syndrome, a rare disorder characterised by the association of neurological defects and renal-glomerular disease. In this study, we demonstrate interaction of WDR73 with the INTS9 and INTS11 components of Integrator, a large multiprotein complex with various roles in RNA metabolism and transcriptional control. We implicate WDR73 in two Integrator-regulated cellular pathways; namely, the processing of uridylate-rich small nuclear RNAs (UsnRNA), and mediating the transcriptional response to epidermal growth factor stimulation. We also show that WDR73 suppression leads to altered expression of genes encoding cell cycle regulatory proteins. Altogether, our results suggest that a range of cellular pathways are perturbed by WDR73 loss-of-function, and support the consensus that proper regulation of UsnRNA maturation, transcription initiation and cell cycle control are all critical in maintaining the health of post-mitotic cells such as glomerular podocytes and neurons, and preventing degenerative disease.
Highlights
Several studies have reported WDR73 mutations to be causative of Galloway–Mowat syndrome, a rare disorder characterised by the association of neurological defects and renal-glomerular disease
WDR73 is a protein predicted to contain six WD40 repeats, these latter being known to mediate diverse protein–protein or protein-DNA interactions (Fig. 1A).To further understand in which cellular pathways WDR73 participates in, we first performed a proteomic analysis of green fluorescent protein (GFP) immunoprecipitates isolated from a conditionally immortalised human podocyte cell line stably expressing GFP-WDR73 full length (Supplementary Fig. S1)
Among the 29 proteins identified as putative WDR73-interacting proteins (Supplementary Table S1), the two most significantly enriched proteins in the GFP-WDR73 were Integrator complex subunit 9 (INTS9) and Integrator complex subunit 11 [INTS11, otherwise known as cleavage and polyadenylation specificity factor-3 like (CPSF3L)]
Summary
Several studies have reported WDR73 mutations to be causative of Galloway–Mowat syndrome, a rare disorder characterised by the association of neurological defects and renal-glomerular disease. Hereditary SRNS generally occurs following mutation of genes encoding proteins required for podocyte functions; podocytes being specialised epithelial cells which form part of the glomerular filtration barrier[5] Both neurons and podocytes are highly differentiated post-mitotic cells, and share several morphological similarities, including an elaborate cytoskeleton and specialised cell–cell junctions[6]. GAMOS patients with WDR73 mutations are affected by a particular subset of the disorder, typically presenting with post-natal progressive microcephaly, ataxia with cerebellar degeneration, and sometimes epilepsy and optic atrophy[8] Renal disease in these patients tends to be of later and more variable age of onset compared to patients with mutations in genes encoding, for example, the KEOPS complex[12].
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