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

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 Integra...

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Autores principales:	F. C. Tilley, C. Arrondel, C. Chhuon, M. Boisson, N. Cagnard, M. Parisot, G. Menara, N. Lefort, I. C. Guerrera, C. Bole-Feysot, A. Benmerah, C. Antignac, G. Mollet
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/167c8a987f01465c88c9cb66da245073
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spelling	oai:doaj.org-article:167c8a987f01465c88c9cb66da2450732021-12-02T11:37:22ZDisruption of pathways regulated by Integrator complex in Galloway–Mowat syndrome due to WDR73 mutations10.1038/s41598-021-84472-72045-2322https://doaj.org/article/167c8a987f01465c88c9cb66da2450732021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-84472-7https://doaj.org/toc/2045-2322Abstract 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.F. C. TilleyC. ArrondelC. ChhuonM. BoissonN. CagnardM. ParisotG. MenaraN. LefortI. C. GuerreraC. Bole-FeysotA. BenmerahC. AntignacG. MolletNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q F. C. Tilley C. Arrondel C. Chhuon M. Boisson N. Cagnard M. Parisot G. Menara N. Lefort I. C. Guerrera C. Bole-Feysot A. Benmerah C. Antignac G. Mollet Disruption of pathways regulated by Integrator complex in Galloway–Mowat syndrome due to WDR73 mutations
description	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.
format	article
author	F. C. Tilley C. Arrondel C. Chhuon M. Boisson N. Cagnard M. Parisot G. Menara N. Lefort I. C. Guerrera C. Bole-Feysot A. Benmerah C. Antignac G. Mollet
author_facet	F. C. Tilley C. Arrondel C. Chhuon M. Boisson N. Cagnard M. Parisot G. Menara N. Lefort I. C. Guerrera C. Bole-Feysot A. Benmerah C. Antignac G. Mollet
author_sort	F. C. Tilley
title	Disruption of pathways regulated by Integrator complex in Galloway–Mowat syndrome due to WDR73 mutations
title_short	Disruption of pathways regulated by Integrator complex in Galloway–Mowat syndrome due to WDR73 mutations
title_full	Disruption of pathways regulated by Integrator complex in Galloway–Mowat syndrome due to WDR73 mutations
title_fullStr	Disruption of pathways regulated by Integrator complex in Galloway–Mowat syndrome due to WDR73 mutations
title_full_unstemmed	Disruption of pathways regulated by Integrator complex in Galloway–Mowat syndrome due to WDR73 mutations
title_sort	disruption of pathways regulated by integrator complex in galloway–mowat syndrome due to wdr73 mutations
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/167c8a987f01465c88c9cb66da245073
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Disruption of pathways regulated by Integrator complex in Galloway–Mowat syndrome due to WDR73 mutations

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