PIK3R4-gene

The PIK3R4 gene (PIK3R4 = acronym for phosphoinositide 3-kinase regulatory subunit 4) is located on chromosome 3q22.1 and encodes the protein phosphoinositide 3-kinase regulatory subunit 4, a regulatory subunit of the PI3K complex that mediates the formation of phosphatidylinositol-3-phosphate. Different forms of the complex are thought to play a role in several membrane trafficking pathways, such at the assembly of autophagosomes. Evidence suggests:

• PI3KC3-C1 is involved in the initiation of autophagosomes.
• PI3KC3-C2 in the maturation of autophagosomes and endocytosis.

Missense mutations in PIK3R4 (phosphoinositide 3-kinase regulatory subunit 4, called VPS15) can lead to ciliopathies. This is a group of diseases that affect the kidney and retina, among others.

Stoetzel et al (2016) found that skin fibroblasts from patients with the arg998-to-gln (R998Q) mutation of the PIK3R4 gene exhibit a ciliary phenotype characterized by shorter primary cilia. Several studies showed that human VPS15 interacts with the Golgin GM130 and is localized in the Golgi. Stoetzel et al. (2016) concluded that VPS15 and GM130 form a complex in the Golgi that ensures IFT20-dependent sorting and transport of membrane proteins from the cis-Golgi to the primary cilium.

1. Gstrein T et al. (2018) Mutations in Vps15 perturb neuronal migration in mice and are associated with neurodevelopmental disease in humans. Nature Neurosci 21: 207-217
2. Panaretou C et al (1997) Characterization of p150, an adaptor protein for the human phosphatidylinositol (PtdIns) 3-kinase: substrate presentation by phosphatidylinositol transfer protein to the p150-PtdIns 3-kinase complex. J Biol Chem 272: 2477-2485
3. Stoetzel C et al (2016) A mutation in VPS15 (PIK3R4) causes a ciliopathy and affects IFT20 release from the cis-Golgi. Nature Commun 7: 13586