Investigation of Mechanisms Linking PIK3R1 Mutations to Metabolic Diseases. (360G-Wellcome-102356_Z_13_Z)

Phosphoinositide 3-kinase (PI3K) is involved in metabolic and mitogenic signalling pathways. Heterozygous autosomal dominant mutations of Class IA PI3K regulatory subunits (PIK3R1), p85alpha, p50alpha and p55alpha, have been identified in patients with SHORT syndrome. This is a rare monogenic disease characterised by a variety of abnormalities including insulin resistance (IR) and hyperglycaemia. Research within the Semple group has focussed on in vitro and in vivo studies of the SHORT mutation Y657X (Y, tyrosine; X, stop codon) of p85alpha. Previous work has not succeeded in deciphering the mechanisms causing the disease phenotype, and this project aims to develop our understanding of how PIK3R1 mutations lead to IR exhibited by patients with SHORT syndrome. It is hypothesised that insulin signalling defects may be facilitated by the shorter splice variants, p50alpha or p55alpha, and that these mutations alter regulation of p110beta-mediated pathways. Additionally, it is proposed that IR occurs in a cell-specific manner from either hepatocytes or adipocytes. Furthermore, PIK3R1 mutations are associated with