Disruption of pathways regulated by Integrator complex in Galloway–Mowat syndrome due to WDR73 mutations
Open Access
- 8 March 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Scientific Reports
- Vol. 11 (1), 1-13
- https://doi.org/10.1038/s41598-021-84472-7
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.Funding Information
- Fondation pour la Recherche Médicale (DEQ2015031682)
- Seventh Framework Programme (FP7/2012, grant 305608 EURenOmics)
- Agence Nationale de la Recherche (ANR-10-IAHU-01, ANR-18-CE11-0008-02)
This publication has 49 references indexed in Scilit:
- The super elongation complex (SEC) family in transcriptional controlNature Reviews Molecular Cell Biology, 2012
- snRNA 3′ End Formation Requires Heterodimeric Association of Integrator SubunitsMolecular and Cellular Biology, 2012
- Mutations in U4atac snRNA, a Component of the Minor Spliceosome, in the Developmental Disorder MOPD IScience, 2011
- Proteomic analysis of the slit diaphragm complex: CLIC5 is a protein critical for podocyte morphology and functionKidney International, 2010
- Linking actin dynamics and gene transcription to drive cellular motile functionsNature Reviews Molecular Cell Biology, 2010
- p21 in cancer: intricate networks and multiple activitiesNature Reviews Cancer, 2009
- Cell-cycle regulatory proteins in the podocyte in collapsing glomerulopathy in childrenKidney International, 2006
- The podocyte's response to injury: Role in proteinuria and glomerulosclerosisKidney International, 2006
- Differential requirement of EGF receptor and its tyrosine kinase for AP-1 transactivation induced by EGF and TPAOncogene, 2003
- The Hallmarks of CancerCell, 2000