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

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.

• Authors: Manuela Wiessner, Andreas Roos, Christopher J Munn, Ranjith Viswanathan, Tamieka Whyte, Dan Cox, Benedikt Schoser, Caroline Sewry, Helen Roper, Rahul Phadke, Chiara Marini Bettolo, Rita Barresi, Richard Charlton, Carsten G Bönnemann, Osório Abath Neto, Umbertina C Reed, Edmar Zanoteli, Cristiane Araújo Martins Moreno, Birgit Ertl-Wagner, Rolf Stucka, Christian De Goede, Tamiris Borges da Silva, Denisa Hathazi, Margherita Dell'Aica, René P Zahedi, Simone Thiele, Juliane Müller, Helen Kingston, Susanna Müller, Elizabeth Curtis, Maggie C Walter, Tim M Strom, Volker Straub, Kate Bushby, Francesco Muntoni, Laura E Swan, Hanns Lochmüller, Jan Senderek
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 100 Issue 3 Pg. 523-536 (Mar 02 2017) ISSN: 1537-6605 [Electronic] United States
• PMID: 28190456 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• SKIP enzyme, human
• Phosphoric Monoester Hydrolases

Topics

• Adolescent
• Adult
• Alleles
• Animals
• Brain (pathology)
• Cataract (genetics)
• Child
• Child, Preschool
• Cognitive Dysfunction (genetics)
• Disease Models, Animal
• Down-Regulation
• Female
• Genome-Wide Association Study
• Humans
• Infant
• Intellectual Disability (genetics)
• Magnetic Resonance Imaging
• Male
• Muscle, Skeletal (pathology)
• Muscular Dystrophies, Limb-Girdle (genetics)
• Musculoskeletal Abnormalities (genetics)
• Mutation
• Pedigree
• Phosphoric Monoester Hydrolases (genetics)
• Young Adult
• Zebrafish (embryology, genetics)