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Lookup NU author(s): Dr Andreas Roos, Daniel CoxORCiD, Professor Chiara Marini Bettolo, Dr Rita Barresi, Dr Richard Charlton, Dr Juliane Mueller, Professor Volker StraubORCiD, Emerita Professor Katherine Bushby, Professor Hanns Lochmuller
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2017 The Author(s) Phosphoinositides are small phospholipids that control diverse cellular downstream signaling events. Their spatial and temporal availability is tightly regulated by a set of specific lipid kinases and phosphatases. Congenital muscular dystrophies are hereditary disorders characterized by hypotonia and weakness from birth with variable eye and central nervous system involvement. In individuals exhibiting congenital muscular dystrophy, early-onset cataracts, and mild intellectual disability but normal cranial magnetic resonance imaging, we identified bi-allelic mutations in INPP5K, encoding inositol polyphosphate-5-phosphatase K. Mutations impaired phosphatase activity toward the phosphoinositide phosphatidylinositol (4,5)-bisphosphate or altered the subcellular localization of INPP5K. Downregulation of INPP5K orthologs in zebrafish embryos disrupted muscle fiber morphology and resulted in abnormal eye development. These data link congenital muscular dystrophies to defective phosphoinositide 5-phosphatase activity that is becoming increasingly recognized for its role in mediating pivotal cellular mechanisms contributing to disease.
Author(s): Wiessner M, Roos A, Munn CJ, Viswanathan R, Whyte T, Cox D, Schoser B, Sewry C, Roper H, Phadke R, Marini Bettolo C, Barresi R, Charlton R, Bonnemann CG, Abath Neto O, Reed UC, Zanoteli E, Araujo Martins Moreno C, Ertl-Wagner B, Stucka R, De Goede C, Borges da Silva T, Hathazi D, Dell'Aica M, Zahedi RP, Thiele S, Muller J, Kingston H, Muller S, Curtis E, Walter MC, Strom TM, Straub V, Bushby K, Muntoni F, Swan LE, Lochmuller H, Senderek J
Publication type: Article
Publication status: Published
Journal: American Journal of Human Genetics
Year: 2017
Volume: 100
Issue: 3
Pages: 523-536
Print publication date: 02/03/2017
Online publication date: 09/02/2017
Acceptance date: 12/01/2017
Date deposited: 24/04/2017
ISSN (print): 0002-9297
ISSN (electronic): 1537-6605
Publisher: Cell Press
URL: https://doi.org/10.1016/j.ajhg.2017.01.024
DOI: 10.1016/j.ajhg.2017.01.024
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