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. At the cellular level, PIK3C2A is critical for the formation of cilia and for receptor mediated endocytosis, among other biological functions. 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. In particular, the considerable phenotypic overlap, yet distinct features, between this syndrome and Lowe’s syndrome, which is caused by mutations in the PI-5-phosphatase OCRL , highlight the key role of PI metabolizing enzymes in specific developmental processes and demonstrate the unique non-redundant functions of each enzyme. 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.

Phosphoinositide lipids in primary cilia biology

“…These phenotypes are consistent with the impaired Smoothened and polycystin-2 cilia trafficking [9,73]. Furthermore, fibroblasts from subjects with the novel PIK3C2A mutant ciliopathy-like syndrome exhibit shorter cilia with reduced PtdIns(3)P and Rab11 levels at the cilia base [75]. In renal epithelial cells this cilia base endosomal PtdIns(3)P pool is increased by shear stress in a PI3K-C2α-dependent manner to recruit autophagy mediators and thereby activates a non-canonical shear stress-induced autophagy program [137].…”

“…Many features of this syndrome are similar to classical ciliopathy syndromes [30] and closely resemble Lowe's syndrome, a ciliopathy-associated disorder with mutations in the cilia-localised 5-phosphatase OCRL discussed below [76,77]. Similar to Pik3c2a-null cells, PIK3C2A mutant human fibroblasts exhibit reduced cilia length, suggesting that this PIK3C2A mutant syndrome may represent a new ciliopathy [75].…”

“…A novel human syndrome defined by skeletal malformations, short stature, cataracts and developmental delay was recently associated with homozygous PIK3C2A mutations [75]. All mutations identified to date are thought to be loss-of-function and result in a loss of protein expression [75]. Many features of this syndrome are similar to classical ciliopathy syndromes [30] and closely resemble Lowe's syndrome, a ciliopathy-associated disorder with mutations in the cilia-localised 5-phosphatase OCRL discussed below [76,77].…”

“…A novel human syndrome defined by skeletal malformations, short stature, cataracts and developmental delay was recently associated with homozygous PIK3C2A mutations [75]. All mutations identified to date are thought to be loss-of-function and result in a loss of protein expression [75].…”

CNV-based genome-wide association studies with performance traits in broilers

“…A very high degree of synteny is maintained between MyoD1 containing regions of human chromosome 11 and chicken chromosome 5, comprising ABCC8, KCNJ11, PIK3C2A, RPS13, SERGEF, NUCB2 and PLEKHA7 genes [135]. Mutations in PIK3C2A gene were discovered to cause a growth-related genetic syndrome in humans, consisting of dysmorphic features, short stature and skeletal abnormalities [136]. This gene has been attributed to biological functions such as glucose transport, Akt pathway activation, endosomal trafficking, phagosome maturation, mitotic spindle organization, exocytosis and autophagy [137][138][139][140][141][142][143].…”