Mutations in PIK3C2A cause syndromic short stature, skeletal abnormalities, and cataracts associated with ciliary dysfunction.

Dov Tiosano,Volker Haucke,Antje Wiesener,Adi Mory,Anlu Chen,Ronald Roepman,Christian T Thiel,Brett Copeland,David A Buchner,Marrit M Hitzert,Rolph Pfundt,Josh Kriwinsky,Karl X Knaup,Michael S Wiesener,Emilio Hirsch,Federico Gulluni,Markus Schueler,André Reis,Hagit N Baris,Patrick Rump,Antonio Bergua,Joseph G Gleeson,Hester Van Meer,Mariam G Aslanyan ,Nadine Hauer ,Deborah A Sival

doi:10.1371/journal.pgen.1008088

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.

Highlights

Identifying the genetic basis of diseases with Mendelian inheritance provides insight into gene function, susceptibility to disease, and can guide the development of new therapeutics
It is estimated that the genetic basis of approximately one-half of all rare genetic disorders remains unknown
We describe one such rare disorder based on genetic and clinical evaluations of individuals from 3 unrelated consanguineous families with a similar constellation of features including short stature, coarse facial features, cataracts with secondary glaucoma, multiple skeletal abnormalities, neurological manifestations including stroke, among other findings

Summary

Introduction

Identifying the genetic basis of diseases with Mendelian inheritance provides insight into gene function, susceptibility to disease, and can guide the development of new therapeutics. Technological advances in DNA sequencing have facilitated the identification of novel genetic mutations that result in rare Mendelian disorders [3,4] We have applied these next-generation sequencing technologies to discover mutations in PIK3C2A that cause a newly identified genetic syndrome consisting of dysmorphic features, short stature, cataracts and skeletal abnormalities. PI(3)P, PI(3,4)P2, and the other polyphosphoinositides each account for less than ~1% of the total phospholipid content of a cell [8] Despite their relatively low abundance, they play central roles in a broad array of signaling pathways and are Mutations in PIK3C2A cause syndromic short stature central to the pathophysiology underlying cancer, metabolic disease, and host-pathogen interactions [6]

Methods

Results

Discussion

Conclusion