RT Journal Article
SR Electronic
T1 Mutations In <em>PIK3C2A</em> Cause Syndromic Short Stature, Skeletal Abnormalities, and Cataracts Associated With Ciliary Dysfunction
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 488411
DO 10.1101/488411
A1 Dov Tiosano
A1 Hagit Baris Feldman
A1 Anlu Chen
A1 Marrit M. Hitzert
A1 Markus Schueler
A1 Federico Gulluni
A1 Antje Wiesener
A1 Antonio Bergua
A1 Adi Mory
A1 Brett Copeland
A1 Joseph G. Gleeson
A1 Patrick Rump
A1 Hester van Meer
A1 Deborah A. Sival
A1 Volker Haucke
A1 Josh Kriwinsky
A1 Karl X. Knaup
A1 André Reis
A1 Nadine N. Hauer
A1 Emilio Hirsch
A1 Ronald Roepman
A1 Rolph Pfundt
A1 Christian T. Thiel
A1 Michael S. Wiesener
A1 Mariam G. Aslanyan
A1 David A. Buchner
YR 2018
UL http://biorxiv.org/content/early/2018/12/07/488411.abstract
AB 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. 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. 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.