ZFIN ID: ZDB-PUB-161125-3
A mutation in VPS15 (PIK3R4) causes a ciliopathy and affects IFT20 release from the cis-Golgi
Stoetzel, C., Bär, S., De Craene, J.O., Scheidecker, S., Etard, C., Chicher, J., Reck, J.R., Perrault, I., Geoffroy, V., Chennen, K., Strähle, U., Hammann, P., Friant, S., Dollfus, H.
Date: 2016
Source: Nature communications   7: 13586 (Journal)
Registered Authors: Etard, Christelle, Strähle, Uwe
Keywords: Ciliogenesis, Disease genetics, Golgi, Mechanisms of disease
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
  • Craniofacial Abnormalities/genetics
  • Female
  • Fibroblasts/metabolism
  • Golgi Apparatus/metabolism*
  • Hand Deformities, Congenital/complications
  • Hand Deformities, Congenital/genetics
  • Humans
  • Learning Disabilities/complications
  • Learning Disabilities/genetics
  • Male
  • Mutation
  • Mutation, Missense
  • Renal Insufficiency/complications
  • Renal Insufficiency/genetics
  • Retinitis Pigmentosa/complications
  • Retinitis Pigmentosa/genetics
  • Saccharomyces cerevisiae
  • Siblings
  • Skin/cytology
  • Vacuolar Sorting Protein VPS15/genetics*
  • Young Adult
  • Zebrafish
PubMed: 27882921 Full text @ Nat. Commun.
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.