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

• Published in: Nature communications 2016-11, Vol.7 (1), p.13586-13586, Article 13586
• Main Authors: Stoetzel, Corinne, Bär, Séverine, De Craene, Johan-Owen, Scheidecker, Sophie, Etard, Christelle, Chicher, Johana, Reck, Jennifer R., Perrault, Isabelle, Geoffroy, Véronique, Chennen, Kirsley, Strähle, Uwe, Hammann, Philippe, Friant, Sylvie, Dollfus, Hélène
• Format: Article
• Language: English
• Subjects: 13; 14/19; 14/63; 631/136/2432; 631/208/2489/144; 631/80/304; 631/80/313/1525; 64; 64/116; 82; Abnormalities, Multiple - genetics; Adolescent; Animals; Autophagy; Biotechnology; Carrier Proteins - metabolism; Case-Control Studies; Cells, Cultured; Cellular Biology; Child; Child, Preschool; Cilia - metabolism; Ciliopathies - genetics; Craniofacial Abnormalities - complications; Craniofacial Abnormalities - genetics; Female; Fibroblasts - metabolism; Genetics; Genotype & phenotype; Golgi Apparatus - metabolism; Hand Deformities, Congenital - complications; Hand Deformities, Congenital - genetics; Humanities and Social Sciences; Humans; Kidneys; Kinases; Learning Disorders - complications; Learning Disorders - genetics; Life Sciences; Localization; Male; multidisciplinary; Mutation; Mutation, Missense; Proteins; Renal Insufficiency - complications; Renal Insufficiency - genetics; Retinitis Pigmentosa - complications; Retinitis Pigmentosa - genetics; Saccharomyces cerevisiae; Science; Science (multidisciplinary); Siblings; Skin - cytology; Subcellular Processes; Vacuolar Sorting Protein VPS15 - genetics; Yeast; Young Adult; Zebrafish
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms13586

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. VPS15 is known as a VPS34-associated protein that functions in intracellular trafficking and autophagy. Here the authors identify a role for VPS15 in ciliopathy and ciliary phenotypes, and show that it interacts with GM130 and functions in IFT20-dependent cis -Golgi to cilium trafficking.