title: A mutation in VPS15 (PIK3R4) causes a ciliopathy and affects IFT20 release from the cis-Golgi.
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.
authors.affiliation: Medical Genetics Laboratory, INSERM U1112, Institute of Medical Genetics of Alsace, University of Strasbourg, Strasbourg Medical School, 67000 Strasbourg, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Stoetzel
authors.affiliation: Department of Molecular and Cellular Genetics, UMR7156, Centre National de Recherche Scientifique (CNRS), Université de Strasbourg, 67084 Strasbourg, France.
authors.forename: Séverine
authors.initials: S
authors.lastname: Bär
authors.affiliation: Department of Molecular and Cellular Genetics, UMR7156, Centre National de Recherche Scientifique (CNRS), Université de Strasbourg, 67084 Strasbourg, France.
authors.forename: Johan-Owen
authors.identifier: 0000-0001-9654-2143
authors.initials: JO
authors.lastname: De Craene
authors.affiliation: Medical Genetics Laboratory, INSERM U1112, Institute of Medical Genetics of Alsace, University of Strasbourg, Strasbourg Medical School, 67000 Strasbourg, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Scheidecker
authors.affiliation: Institut für Toxikologie und Genetik, Campus Nord, Karlsruher Institut für Technologie, Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein Leopoldshafen, Germany.
authors.forename: Christelle
authors.initials: C
authors.lastname: Etard
authors.affiliation: Institut de Biologie Moléculaire et Cellulaire (IBMC), Plateforme Protéomique Strasbourg-Esplanade, CNRS FRC1589, 67084 Strasbourg, France.
authors.forename: Johana
authors.initials: J
authors.lastname: Chicher
authors.affiliation: Department of Molecular and Cellular Genetics, UMR7156, Centre National de Recherche Scientifique (CNRS), Université de Strasbourg, 67084 Strasbourg, France.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Reck
authors.affiliation: Laboratory of Genetics in Ophthalmology, INSERM UMR1163, Institut Imagine, Université Paris Descartes Sorbonne Paris Cité, Hôpital Necker, 75015 Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Perrault
authors.affiliation: Medical Genetics Laboratory, INSERM U1112, Institute of Medical Genetics of Alsace, University of Strasbourg, Strasbourg Medical School, 67000 Strasbourg, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Geoffroy
authors.affiliation: Medical Genetics Laboratory, INSERM U1112, Institute of Medical Genetics of Alsace, University of Strasbourg, Strasbourg Medical School, 67000 Strasbourg, France.
authors.forename: Kirsley
authors.initials: K
authors.lastname: Chennen
authors.affiliation: Institut für Toxikologie und Genetik, Campus Nord, Karlsruher Institut für Technologie, Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein Leopoldshafen, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Strähle
authors.affiliation: Institut de Biologie Moléculaire et Cellulaire (IBMC), Plateforme Protéomique Strasbourg-Esplanade, CNRS FRC1589, 67084 Strasbourg, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Hammann
authors.affiliation: Department of Molecular and Cellular Genetics, UMR7156, Centre National de Recherche Scientifique (CNRS), Université de Strasbourg, 67084 Strasbourg, France.
authors.forename: Sylvie
authors.identifier: 0000-0002-5412-6288
authors.initials: S
authors.lastname: Friant
authors.affiliation: Medical Genetics Laboratory, INSERM U1112, Institute of Medical Genetics of Alsace, University of Strasbourg, Strasbourg Medical School, 67000 Strasbourg, France.|Centre de Référence pour les affections rares en génétique ophtalmologique, CARGO, Filière SENSGENE, Hôpitaux Universitaires de Strasbourg, 67091 Strasbourg, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Dollfus
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics; D000293:Adolescent; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D016022:Case-Control Studies; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D002923:Cilia / Q000378:metabolism*; D000072661:Ciliopathies / Q000235:genetics*; D019465:Craniofacial Abnormalities / Q000150:complications / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism*; D006228:Hand Deformities, Congenital / Q000150:complications / Q000235:genetics; D006801:Humans; D007859:Learning Disabilities / Q000150:complications / Q000235:genetics; D008297:Male; D009154:Mutation; D020125:Mutation, Missense; D051437:Renal Insufficiency / Q000150:complications / Q000235:genetics; D012174:Retinitis Pigmentosa / Q000150:complications / Q000235:genetics; D012441:Saccharomyces cerevisiae; D035781:Siblings; D012867:Skin / Q000166:cytology; D058571:Vacuolar Sorting Protein VPS15 / Q000235:genetics*; D055815:Young Adult; D015027:Zebrafish
chemical_list: D002352:Carrier Proteins; C487991:IFT20 protein, human; C546851:PIK3R4 protein, human; D058571:Vacuolar Sorting Protein VPS15