A mutation in VPS15 (PIK3R4) causes a ciliopathy and affects IFT20 release from the cis-Golgi

Corinne Stoetzel, Séverine Bär, Johan-Owen De Craene, Sophie Scheidecker, Christelle Etard, Johana Chicher, Jennifer R. Reck, Isabelle Perrault, Véronique Geoffroy, Kirsley Chennen, Uwe Strähle, Philippe Hammann, Sylvie Friant () and Hélène Dollfus ()
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Corinne Stoetzel: Medical Genetics Laboratory, INSERM U1112, Institute of Medical Genetics of Alsace, University of Strasbourg, Strasbourg Medical School
Séverine Bär: UMR7156, Centre National de Recherche Scientifique (CNRS), Université de Strasbourg
Johan-Owen De Craene: UMR7156, Centre National de Recherche Scientifique (CNRS), Université de Strasbourg
Sophie Scheidecker: Medical Genetics Laboratory, INSERM U1112, Institute of Medical Genetics of Alsace, University of Strasbourg, Strasbourg Medical School
Christelle Etard: Institut für Toxikologie und Genetik, Campus Nord, Karlsruher Institut für Technologie
Johana Chicher: Institut de Biologie Moléculaire et Cellulaire (IBMC), Plateforme Protéomique Strasbourg—Esplanade, CNRS FRC1589
Jennifer R. Reck: UMR7156, Centre National de Recherche Scientifique (CNRS), Université de Strasbourg
Isabelle Perrault: Laboratory of Genetics in Ophthalmology, INSERM UMR1163, Institut Imagine, Université Paris Descartes Sorbonne Paris Cité, Hôpital Necker
Véronique Geoffroy: Medical Genetics Laboratory, INSERM U1112, Institute of Medical Genetics of Alsace, University of Strasbourg, Strasbourg Medical School
Kirsley Chennen: Medical Genetics Laboratory, INSERM U1112, Institute of Medical Genetics of Alsace, University of Strasbourg, Strasbourg Medical School
Uwe Strähle: Institut für Toxikologie und Genetik, Campus Nord, Karlsruher Institut für Technologie
Philippe Hammann: Institut de Biologie Moléculaire et Cellulaire (IBMC), Plateforme Protéomique Strasbourg—Esplanade, CNRS FRC1589
Sylvie Friant: UMR7156, Centre National de Recherche Scientifique (CNRS), Université de Strasbourg
Hélène Dollfus: Medical Genetics Laboratory, INSERM U1112, Institute of Medical Genetics of Alsace, University of Strasbourg, Strasbourg Medical School

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: Abstract Ciliopathies are a group of diseases that affect kidney and retina among other organs. Here, we identify a missense mutation in PIK3R4 (phosphoinositide 3-kinase regulatory subunit 4, named VPS15) in a family with a ciliopathy phenotype. Besides being required for trafficking and autophagy, we show that VPS15 regulates primary cilium length in human fibroblasts, as well as ciliary processes in zebrafish. Furthermore, we demonstrate its interaction with the golgin GM130 and its localization to the Golgi. The VPS15-R998Q patient mutation impairs Golgi trafficking functions in humanized yeast cells. Moreover, in VPS15-R998Q patient fibroblasts, the intraflagellar transport protein IFT20 is not localized to vesicles trafficking to the cilium but is restricted to the Golgi. Our findings suggest that at the Golgi, VPS15 and GM130 form a protein complex devoid of VPS34 to ensure the IFT20-dependent sorting and transport of membrane proteins from the cis-Golgi to the primary cilium.

Date: 2016
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DOI: 10.1038/ncomms13586

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