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PMID: 27882921 Published · epublish English Journal Article Research Support, Non-U.S. Gov't

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

Nature communications ·Vol. 7 ·2016-00-24 ·Pages 13586

Stoetzel C, Bär S, De Craene JO, Scheidecker S, Etard C, Chicher J, Reck JR, Perrault I, Geoffroy V, Chennen K, Strähle U, Hammann P, Friant S, Dollfus H

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.

MeSH Terms
Abnormalities, Multiple/genetics Adolescent Animals Carrier Proteins/metabolism Case-Control Studies Cells, Cultured Child Child, Preschool Cilia/metabolism Ciliopathies/genetics Craniofacial Abnormalities/complications,genetics Female Fibroblasts/metabolism Golgi Apparatus/metabolism Hand Deformities, Congenital/complications,genetics Humans Learning Disabilities/complications,genetics Male Mutation Mutation, Missense Renal Insufficiency/complications,genetics Retinitis Pigmentosa/complications,genetics Saccharomyces cerevisiae Siblings Skin/cytology Vacuolar Sorting Protein VPS15/genetics Young Adult Zebrafish
Chemicals
Carrier Proteins IFT20 protein, human PIK3R4 protein, human Vacuolar Sorting Protein VPS15
Authors & Affiliations
14 authors, click to expand affiliations / ORCID
Stoetzel Corinne
Medical Genetics Laboratory, INSERM U1112, Institute of Medical Genetics of Alsace, University of Strasbourg, Strasbourg Medical School, 67000 Strasbourg, France.
Bär Séverine
Department of Molecular and Cellular Genetics, UMR7156, Centre National de Recherche Scientifique (CNRS), Université de Strasbourg, 67084 Strasbourg, France.
De Craene Johan-Owen ORCID
Department of Molecular and Cellular Genetics, UMR7156, Centre National de Recherche Scientifique (CNRS), Université de Strasbourg, 67084 Strasbourg, France.
Scheidecker Sophie
Medical Genetics Laboratory, INSERM U1112, Institute of Medical Genetics of Alsace, University of Strasbourg, Strasbourg Medical School, 67000 Strasbourg, France.
Etard Christelle
Institut für Toxikologie und Genetik, Campus Nord, Karlsruher Institut für Technologie, Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein Leopoldshafen, Germany.
Chicher Johana
Institut de Biologie Moléculaire et Cellulaire (IBMC), Plateforme Protéomique Strasbourg-Esplanade, CNRS FRC1589, 67084 Strasbourg, France.
Reck Jennifer R
Department of Molecular and Cellular Genetics, UMR7156, Centre National de Recherche Scientifique (CNRS), Université de Strasbourg, 67084 Strasbourg, France.
Perrault Isabelle
Laboratory of Genetics in Ophthalmology, INSERM UMR1163, Institut Imagine, Université Paris Descartes Sorbonne Paris Cité, Hôpital Necker, 75015 Paris, France.
Geoffroy Véronique
Medical Genetics Laboratory, INSERM U1112, Institute of Medical Genetics of Alsace, University of Strasbourg, Strasbourg Medical School, 67000 Strasbourg, France.
Chennen Kirsley
Medical Genetics Laboratory, INSERM U1112, Institute of Medical Genetics of Alsace, University of Strasbourg, Strasbourg Medical School, 67000 Strasbourg, France.
Strähle Uwe
Institut für Toxikologie und Genetik, Campus Nord, Karlsruher Institut für Technologie, Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein Leopoldshafen, Germany.
Hammann Philippe
Institut de Biologie Moléculaire et Cellulaire (IBMC), Plateforme Protéomique Strasbourg-Esplanade, CNRS FRC1589, 67084 Strasbourg, France.
Friant Sylvie ORCID
Department of Molecular and Cellular Genetics, UMR7156, Centre National de Recherche Scientifique (CNRS), Université de Strasbourg, 67084 Strasbourg, France.
Dollfus Hélène
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.
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Article Info
Journal
Nature communications
Abbr.
Nat Commun
ISSN
2041-1723
DOI
10.1038/ncomms13586
Published
2016-00-24
Epub
2016-00-24
Pages
13586
Language
English
Region
England
NLM ID
101528555
PMCID
PMC5123056
Subset
IM
Grants
Howard Hughes Medical Institute · United States
External Links
PubMed source DOI: 10.1038/ncomms13586 PMC Full Text View journal details
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