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

Area of Science:

• Cell Biology
• Genetics
• Molecular Medicine

Background:

• Ciliopathies are genetic disorders affecting organs like the kidney and retina, impacting primary cilia function.
• The phosphoinositide 3-kinase regulatory subunit 4 (VPS15) is involved in trafficking and autophagy.

Purpose of the Study:

• To investigate the role of VPS15 in ciliopathies.
• To elucidate the molecular mechanisms by which VPS15 mutations cause disease.

Main Methods:

• Identification of a PIK3R4 (VPS15) missense mutation in a patient family with ciliopathy.
• Functional studies in human fibroblasts and zebrafish to assess VPS15's role in primary cilia.
• Analysis of VPS15 interaction with GM130 and its localization to the Golgi apparatus.
• Assays in humanized yeast cells and patient fibroblasts to evaluate the impact of the VPS15-R998Q mutation on Golgi trafficking and protein localization.

Main Results:

• A VPS15 missense mutation (R998Q) was identified in a family with a ciliopathy phenotype.
• VPS15 regulates primary cilium length in human cells and ciliary processes in zebrafish.
• VPS15 interacts with GM130 at the Golgi, and the R998Q mutation impairs Golgi trafficking.
• The mutation disrupts the localization of intraflagellar transport protein 20 (IFT20) to the Golgi, hindering its transport to the cilium.

Conclusions:

• VPS15 and GM130 form a Golgi-localized complex that is crucial for IFT20-dependent sorting and transport of membrane proteins to primary cilia.
• Disruption of this complex by the VPS15-R998Q mutation leads to ciliopathy.
• This study highlights a novel role for VPS15 in regulating Golgi-to-cilium transport.