PI3Ks are a family of lipid kinases involved in the key processes of cell growth, proliferation, differentiation, motility, survival and intracellular trafficking. The PIK3R5 gene encodes a protein that functions as the regulatory subunit of the heterodimeric PI3K gamma complex. The PIK3R5 protein helps recruit the catalytic subunit of the PI3K complex to the plasma membrane via interaction with beta-gamma G protein dimers. It hence plays an essential role in the formation of the PI3K complex.
Given its crucial role in cellular processes, it is easy to see how defects in the gene can have severe pathological consequences. Mutations in the PIK3R5 gene are associated with Ataxia-Oculomotor Apraxia 3 (AOA3), a cerebellar ataxia characterized by peripheral neuropathy, areflexia, cerebellar atrophy, oculomotor apraxia and raised alpha-fetoprotein levels.
The PIK3R5 gene is located on the short arm of chromosome 17. It spans a length of 86 kb and its coding sequence is made up of 20 exons. The gene encodes a 97 kDa PIK3R5 protein made up of 880 amino acids. The PIK3R5 gene has been found to be ubiquitously expressed at high levels in the fetal human brain. The gene is also expressed at lower levels in the adult human brain, mainly in the cerebellum, cerebral cortex, cerebral meninges and vermis cerebelli. Two distinct isoforms of the PIK3R5 protein exist due to alternative splicing.
So far a single mutation, a homozygous missense variant c.1885C>T (p.P629S) predicted to affect the structure of PIK3R5, has been associated with AOA3.
Al Tassan et al. (2012) analyzed a Saudi family affected by Ataxia with Oculomotor Apraxia. The consanguineous parents had four children affected by AOA2 characteristics, namely impaired ocular movement, areflexia, bilateral atrophy of the cerebella folia and vermis, severe limb and axial dysmetria, elevated alpha-fetoprotein levels as well as moderately severe axonal sensory polyneuropathy with absent sensory nerve action potentials in the lower limbs. An analysis of the SETX gene did not uncover any mutations. Linkage analysis and homozygosity mapping were then used to narrow down the gene locus at 17p12-13. Sequencing of the region revealed a homozygous missense change, c.1885C>T (p.P629S), in exon 12 of the PIK3R5 gene. All affected siblings were homozygous for the mutation while the parents and unaffected siblings were found to be heterozygous. The mutation was not found in 477 ethnically-matched controls. In-silico analysis predicted the mutation to affect the stability and structure of the PIK3R5 protein. An expression analysis of the PIK3R5 gene found it to be highly expressed in the fetal and adult human brain as well as the adult mouse brain.