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

Tiosano D, Baris HN, Chen A, Hitzert MM, Schüler M, Gulluni F, Wiesener A, Bergua A, Mory A, Copeland B, Gleeson JG, Rump P, Van Meer H, Sival DA, Haucke V, Kriwinsky J, Knaup K, Reis A, Hauer N, Hirsch E, Roepman R, Pfundt R, Thiel C, Wiesener MS, Aslanyan MG, Buchner DA (2019)

Publication Type: Journal article

Publication year: 2019

Journal

Book Volume: 15

Pages Range: e1008088-

Journal Issue: 4

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.

Authors with CRIS profile

Involved external institutions

University of Groningen / Rijksuniversiteit Groningen Netherlands (NL) Freie Universität Berlin Germany (DE) Rockefeller University United States (USA) (US) Case Western Reserve University United States (USA) (US) Rambam Health Care Campus Israel (IL) Radboud University Nijmegen Netherlands (NL) University of Turin / Università degli Studi di Torino (UNITO) Italy (IT) Technion - Israel Institute of Technology Israel (IL)

How to cite

APA:

Tiosano, D., Baris, H.N., Chen, A., Hitzert, M.M., Schüler, M., Gulluni, F.,... Buchner, D.A. (2019). Mutations in PIK3C2A cause syndromic short stature, skeletal abnormalities, and cataracts associated with ciliary dysfunction. PLoS Genetics, 15(4), e1008088-. https://dx.doi.org/10.1371/journal.pgen.1008088

MLA:

Tiosano, Dov, et al. "Mutations in PIK3C2A cause syndromic short stature, skeletal abnormalities, and cataracts associated with ciliary dysfunction." PLoS Genetics 15.4 (2019): e1008088-.

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