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


Journal

PLoS genetics
ISSN: 1553-7404
Titre abrégé: PLoS Genet
Pays: United States
ID NLM: 101239074

Informations de publication

Date de publication:
04 2019
Historique:
received: 21 12 2018
accepted: 12 03 2019
revised: 09 05 2019
pubmed: 30 4 2019
medline: 1 10 2019
entrez: 30 4 2019
Statut: epublish

Résumé

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.

Identifiants

pubmed: 31034465
doi: 10.1371/journal.pgen.1008088
pii: PGENETICS-D-18-02416
pmc: PMC6508738
doi:

Substances chimiques

Phosphatidylinositol 3-Kinases EC 2.7.1.-
PIK3C2A protein, human EC 2.7.1.137

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

e1008088

Subventions

Organisme : NIDDK NIH HHS
ID : R03 DK099533
Pays : United States
Organisme : NIDDK NIH HHS
ID : R56 DK112846
Pays : United States

Déclaration de conflit d'intérêts

The authors have declared that no competing interests exist.

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Auteurs

Dov Tiosano (D)

Division of Pediatric Endocrinology, Ruth Children's Hospital, Rambam Medical Center, Haifa, Israel.
Rappaport Family Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.

Hagit N Baris (HN)

Rappaport Family Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
The Genetics Institute, Rambam Health Care Campus, Haifa, Israel.

Anlu Chen (A)

Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio, United States of America.

Marrit M Hitzert (MM)

Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Markus Schueler (M)

Department of Nephrology and Hypertension, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.

Federico Gulluni (F)

Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Turin, Torino, Italy.

Antje Wiesener (A)

Institute of Human Genetics, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.

Antonio Bergua (A)

Department of Ophthalmology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.

Adi Mory (A)

The Genetics Institute, Rambam Health Care Campus, Haifa, Israel.

Brett Copeland (B)

Laboratory of Pediatric Brain Diseases, Rockefeller University, New York, New York, United States of America.

Joseph G Gleeson (JG)

Laboratory of Pediatric Brain Diseases, Rockefeller University, New York, New York, United States of America.
Department of Neurosciences, University of California, San Diego, La Jolla, California, United States of America.

Patrick Rump (P)

Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Hester van Meer (H)

Department of Pediatrics, Beatrix Children's Hospital, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Deborah A Sival (DA)

Department of Pediatrics, Beatrix Children's Hospital, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Volker Haucke (V)

Leibniz-Institut für Molekulare Pharmakologie, Berlin Faculty of Biology, Chemistry, and Pharmacy, Freie Universität Berlin, Berlin, Germany.

Josh Kriwinsky (J)

Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio, United States of America.

Karl X Knaup (KX)

Department of Nephrology and Hypertension, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.

André Reis (A)

Institute of Human Genetics, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.

Nadine N Hauer (NN)

Institute of Human Genetics, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.

Emilio Hirsch (E)

Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Turin, Torino, Italy.

Ronald Roepman (R)

Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.

Rolph Pfundt (R)

Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.

Christian T Thiel (CT)

Institute of Human Genetics, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.

Michael S Wiesener (MS)

Department of Nephrology and Hypertension, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.

Mariam G Aslanyan (MG)

Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.

David A Buchner (DA)

Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio, United States of America.
Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio, United States of America.
Research Institute for Children's Health, Case Western Reserve University, Cleveland, Ohio, United States of America.

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