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

Please always quote using this URN: urn:nbn:de:bvb:29-opus4-118007
  • 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 lackedPIK3C2A 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.show moreshow less

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Author:Dov Tiosano, Hagit N. Baris, Anlu Chen, Marrit M. Hitzert, Markus Schueler, Federico Gulluni, Antje Wiesener, Antonio Bergua, Adi Mory, Brett Copeland, Joseph G. Gleeson, Patrick Rump, Hester van Meer, Deborah A. Sival, Volker Haucke, Josh Kriwinsky, Karl X. Knaup, André Reis, Nadine N. Hauer, Emilio Hirsch, Ronald Roepman, Rolph Pfundt, Christian T. Thiel, Michael S. Wiesener, Mariam G. Aslanyan, David A. Buchner
Persistent identifiers - URN:urn:nbn:de:bvb:29-opus4-118007
Persistent identifiers - DOI:https://doi.org/10.1371/journal.pgen.1008088
Title of the journal / compilation (English):PLoS Genetics
Document Type:Article
Language:English
Year of publication:2019
Date of online publication (Embargo Date):2019/08/28
Publishing Institution:Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU)
Release Date:2019/08/29
Tag:Cataracts; Cilia; Clinical genetics; Enzyme metabolism; Fibroblasts; Magnetic resonance imaging; Metabolic disorders; Mutation detection
Volume/year:15
Issue:4
Original publication:PLoS Genetics 15.4 (2019). <https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1008088>
Institutes:Medizinische Fakultät
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
open_access (DINI-Set):open_access
Collections:Universität Erlangen-Nürnberg / Open Access Artikel ohne Förderung / Open Access Artikel ohne Förderung 2019
Licence (German):Creative Commons - CC BY - Namensnennung 4.0 International
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