Paradoxical dominant negative activity of an immunodeficiency-associated activatingPIK3R1variant

Abstract

PIK3R1encodes three regulatory subunits of class IA phosphoinositide 3-kinase (PI3K), each associating with any of three catalytic subunits, namely p110α, p110β or p110δ. ConstitutionalPIK3R1mutations cause diseases with a genotype-phenotype relationship not yet fully explained: heterozygous loss-of-function mutations cause SHORT syndrome, featuring insulin resistance and short stature attributed to reduced p110α function, while heterozygous activating mutations cause immunodeficiency, attributed to p110δ activation and known as APDS2. Surprisingly, APDS2 patients do not show features of p110α hyperactivation, but do commonly have short stature or SHORT syndrome, suggesting p110α hypofunction. We sought to investigate this. In dermal fibroblasts from an APDS2 patient, we found no increased PI3K signalling, with p110δ expression markedly reduced. In preadipocytes, the APDS2 variant was potently dominant negative, associating with Irs1 and Irs2 but failing to heterodimerise with p110α. This attenuation of p110α signalling by a p110δ-activating PIK3R1 variant potentially explains co-incidence of gain-of-function and loss-of-functionPIK3R1phenotypes.

The metabolically protective energy expenditure increase ofPik3r1-related insulin resistance is not explained by Ucp1-mediated thermogenesis

“…We have developed and described a mouse model of SHORT syndrome caused by the Pikr3r1 Y657* mutation [11]. This mutation leads to truncation of all three protein products of the Pik3r1 gene -P85α/P50α/P55α -in the C-terminal SH2 domain, preventing recruitment of PI3K to phosphorylated tyrosine residues on insulin receptor substrate proteins [7,[12][13][14]. In keeping with this, mice heterozygous for the Pik3r1 Y657* mutation (Pik3r1 Y657* mice) show an attenuated intracellular insulin signalling cascade, and thus severe IR [6,11,15].…”