Mutations In PIK3C2A Cause Syndromic Short Stature, Skeletal Abnormalities, and Cataracts Associated With Ciliary Dysfunction

Abstract

PIK3C2A is a class II member of the phosphoinositide 3-kinase (PI3K) family that catalyzes the phosphorylation of phosphatidylinositol (PI) into PI(3)P and the phosphorylation of PI(4)P into PI(3,4)P2. We identified homozygous loss-of-function mutations in PIK3C2A in children from three independent consanguineous families with short stature, coarse facial features, cataracts with secondary glaucoma, multiple skeletal abnormalities, neurological manifestations, among other findings. Cellular studies of patient-derived fibroblasts found that they lacked PIK3C2A protein, had impaired cilia formation and function, and demonstrated reduced proliferative capacity.Collectively, the genetic and molecular data implicate mutations in PIK3C2A in a new Mendelian disorder of PI metabolism, thereby shedding light on the critical role of a class II PI3K in growth, vision, skeletal formation and neurological development. This discovery expands what is known about disorders of PI metabolism and helps unravel the role of PIK3C2A and class II PI3Ks in health and disease.

PI3K isoforms in cell signalling and vesicle trafficking

“…Whereas this may point to a functional divergence of PI3K-C2α in mice and humans, it should be noted that fibroblasts derived from these patients displayed strongly increased expression of PI3K-C2β. This raises the possibility of a compensatory mechanism not observed in mice 186 .…”

“…Surprisingly, homozygous PI3K-C2α deficiency has recently been reported in a small number of patients presenting with skeletal abnormalities and cataract formation, amongst other symptoms 186 . Whereas this may point to a functional divergence of PI3K-C2α in mice and humans, it should be noted that fibroblasts derived from these patients displayed strongly increased expression of PI3K-C2β.…”

Whole-genome sequencing of European autochthonous and commercial pig breeds allows the detection of signatures of selection for adaptation of genetic resources to different breeding and production systems

“…Another signal was observed on SSC2 (see Additional file 1 : Figure S8d), which contains the PIK3C2A gene. Mutations in the human PIK3C2A gene cause syndromic short stature and skeletal abnormalities [94]. The small vs. Fig.…”

PI3K inhibitors in thrombosis and cardiovascular disease

“…Indeed, PI3KC2α has been shown to regulate angiogenesis, insulin signalling and glucose transport, sonic hedgehog signalling, primary cilium assembly and clathrin‐mediated endocytosis [93, 94, 105, 107–109]. The impact of homozygous loss of PI3KC2α appears to be less severe in humans, potentially reflecting differential usage of Class II PI3Ks between humans and mice, or a differing ability to compensate [110]. Such species difference is an important factor in the consideration of PI3K inhibitor development for human disease.…”