Disruption of pathways regulated by Integrator complex in Galloway-Mowat syndrome due to WDR73 mutations

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.

Automated summary

The study demonstrates the interaction of WDR73 with components of Integrator complex and implicates WDR73 in regulating UsnRNA processing and transcriptional response to epidermal growth factor stimulation. Loss of WDR73 function affects the expression of genes encoding cell cycle regulatory proteins, indicating disturbances in multiple cellular pathways.