Mutations in INPP5K, Encoding a Phosphoinositide 5-Phosphatase, Cause Congenital Muscular Dystrophy with Cataracts and Mild Cognitive Impairment



Weissner, M, Roos, A, Munn, CJ, Viswanathan, R, Whyte, T, Cox, D, Schoser, B, Sewry, C, Rooper, H, Phadke, R
et al (show 28 more authors) (2017) Mutations in INPP5K, Encoding a Phosphoinositide 5-Phosphatase, Cause Congenital Muscular Dystrophy with Cataracts and Mild Cognitive Impairment. American Journal of Human Genetics, 100 (3). 523 - 536.

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Abstract

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.

Item Type: Article
Uncontrolled Keywords: Congenital muscular dystrophy, Early cataracts, Cognitive impairment, INPP5K, Phosphoinositide phosphatase
Depositing User: Symplectic Admin
Date Deposited: 15 Feb 2017 08:25
Last Modified: 25 Nov 2021 15:10
DOI: 10.1016/j.ajhg.2017.01.024
Open Access URL: http://www.cell.com/ajhg/fulltext/S0002-9297(17)30...
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URI: https://livrepository.liverpool.ac.uk/id/eprint/3005024