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

Wiessner, Manuela, Roos, Andreas, Munn, Christopher J, Viswanathan, Ranjith, Whyte, Tamieka, Cox, Dan, Schoser, Benedikt, Sewry, Caroline, Roper, Helen, Phadke, Rahul, Marini Bettolo, Chiara, Barresi, Rita, Charlton, Richard, Bönnemann, Carsten G, Abath Neto, Osório, Reed, Umbertina C, Zanoteli, Edmar, Araújo Martins Moreno, Cristiane, Ertl-Wagner, Birgit, Stucka, Rolf, De Goede, Christian, Borges da Silva, Tamiris, Hathazi, Denisa, Dell'Aica, Margherita, Zahedi, René P, Thiele, Simone, Müller, Juliane, Kingston, Helen, Müller, Susanna, Curtis, Elizabeth, Walter, Maggie C, Strom, Tim M, Straub, Volker, Bushby, Kate, Muntoni, Francesco, Swan, Laura E, Lochmüller, Hanns and Senderek, Jan (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). pp. 523-536. ISSN 1537-6605.

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Official URL: http://www.cell.com/ajhg/issue?pii=S0002-9297(16)X...

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
Subjects: WE Musculoskeletal. Orthopaedics
Divisions: Womens and Childrens > Paediatrics
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Depositing User: Mrs Yolande Brookes
Date Deposited: 25 May 2017 15:20
Last Modified: 25 May 2017 15:20
URI: http://www.repository.uhblibrary.co.uk/id/eprint/1378

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