Paradoxical dominant negative activity of an immunodeficiency-associated activating PIK3R1 variant
PIK3R1 encodes three regulatory subunits of class IA phosphoinositide 3-kinase (PI3K), each associating with any of three catalytic subunits, namely p110, p110{beta} or p110{delta}. Constitutional PIK3R1 mutations 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 p110 function, while heterozygous activating mutations cause immunodeficiency, attributed to p110{delta} activation and known as APDS2. Surprisingly, APDS2 patients do not show features of p110 hyperactivation, but do commonly have SHORT syndrome-like features, suggesting p110 hypofunction. We sought to investigate this. In dermal fibroblasts from an APDS2 patient, we found no increased PI3K signalling, with p110{delta} expression markedly reduced. In preadipocytes, the APDS2 variant was potently dominant negative, associating with Irs1 and Irs2 but failing to heterodimerise with p110. This attenuation of p110 signalling by a p110{delta}-activating PIK3R1 variant potentially explains co-incidence of gain-of-function and loss-of-function PIK3R1 phenotypes.