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

Journal article


Publication Details

Author(s): 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 KX, Reis A, Hauer N, Hirsch E, Roepman R, Pfundt R, Thiel C, Wiesener MS, Aslanyan MG, Buchner DA
Journal: PLoS Genetics
Publication year: 2019
Volume: 15
Journal issue: 4
Pages range: e1008088-
ISSN: 1553-7390
eISSN: 1553-7404


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.


FAU Authors / FAU Editors

Hauer, Nadine
Lehrstuhl für Humangenetik
Knaup, Karl Xaver
Medizinische Klinik 4 - Nephrologie und Hypertensiologie
Schüler, Markus Dr. med.
Medizinische Klinik 4 - Nephrologie und Hypertensiologie
Thiel, Christian PD Dr.
Medizinische Fakultät


External institutions with authors

Case Western Reserve University
Freie Universität Berlin
Radboud University Nijmegen
Rambam Health Care Campus
Rockefeller University
Technion - Israel Institute of Technology
University of Groningen / Rijksuniversiteit Groningen
University of Turin / Università degli Studi di Torino (UNITO)


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-.

BibTeX: 

Last updated on 2019-03-06 at 10:53