Ubiquitous expression of the Pik3caH1047R mutation promotes hypoglycemia, hypoinsulinemia, and organomegaly

Abstract

Mutations in PIK3CA, the gene encoding the p110α catalytic subunit of PI3K, are among the most common mutations found in human cancer and have also recently been implicated in a range of overgrowth syndromes in humans. We have used a novel inducible "exon-switch"approach to knock in the constitutively active Pik3caH1047R mutation into the endogenous Pik3ca gene of the mouse. Ubiquitous expression of the Pik3caH1047Rmutation throughout the body resulted in a dramatic increase in body weight within 3 weeks of induction (mutant 150 ± 5%; wild-type 117 ± 3%, mean ± SEM), which was associated with increased organ size rather than adiposity. Severe metabolic effects, including a reduction in blood..