Journal article
Mutations in INPPSK, Encoding a Phosphoinositide 5-Phosphatase, Cause Congenital Muscular Dystrophy with Cataracts and Mild Cognitive Impairment
American journal of human genetics, Vol.100(3), pp.523-536
03/02/2017
DOI: 10.1016/j.ajhg.2017.01.024
PMCID: PMC5339217
PMID: 28190456
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. Down regulation 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.
Details
- Title: Subtitle
- Mutations in INPPSK, Encoding a Phosphoinositide 5-Phosphatase, Cause Congenital Muscular Dystrophy with Cataracts and Mild Cognitive Impairment
- Creators
- Manuela Wiessner - Ludwig-Maximilians-Universität MünchenAndreas Roos - Newcastle UniversityChristopher J. Munn - University of LiverpoolRanjith Viswanathan - Ludwig-Maximilians-Universität MünchenTamieka Whyte - Great Ormond Street HospitalDan Cox - Newcastle UniversityBenedikt Schoser - Ludwig-Maximilians-Universität MünchenCaroline Sewry - Great Ormond Street HospitalHelen Roper - Heart of England NHS Foundation TrustRahul Phadke - Great Ormond Street HospitalChiara Marini Bettolo - Newcastle UniversityRita Barresi - Newcastle UniversityRichard Charlton - Newcastle UniversityCarsten G. Bonnemann - National Institute of Neurological Disorders and StrokeOsorio Abath Neto - National Institute of Neurological Disorders and StrokeUmbertina C. Reed - Universidade de São PauloEdmar Zanoteli - Universidade de São PauloCristiane Araujo Martins Moreno - Universidade de São PauloBirgit Ertl-Wagner - Ludwig-Maximilians-Universität MünchenRolf Stucka - Ludwig-Maximilians-Universität MünchenChristian De Goede - Lancashire Teaching Hospitals NHS Foundation TrustTamiris Borges da Silva - University of LiverpoolDenisa Hathazi - Leibniz Institute for NeurobiologyMargherita Dell'Aica - Leibniz Institute for Analytical Sciences - ISASRene P. Zahedi - Leibniz Institute for NeurobiologySimone Thiele - Ludwig-Maximilians-Universität MünchenJuliane Muller - Newcastle UniversityHelen Kingston - Manchester University NHS Foundation TrustSusanna Mueller - Ludwig-Maximilians-Universität MünchenElizabeth Curtis - University Hospitals Birmingham NHS Foundation TrustMaggie C. Walter - Ludwig-Maximilians-Universität MünchenTim M. Strom - Technical University of MunichVolker Straub - Newcastle UniversityKate Bushby - Newcastle UniversityFrancesco Muntoni - Great Ormond Street HospitalLaura E. Swan - University of LiverpoolHanns Lochmuller - Newcastle UniversityJan Senderek - Ludwig-Maximilians-Universität München
- Resource Type
- Journal article
- Publication Details
- American journal of human genetics, Vol.100(3), pp.523-536
- DOI
- 10.1016/j.ajhg.2017.01.024
- PMID
- 28190456
- PMCID
- PMC5339217
- NLM abbreviation
- Am J Hum Genet
- ISSN
- 0002-9297
- eISSN
- 1537-6605
- Publisher
- Elsevier
- Number of pages
- 14
- Grant note
- Nationally Commissioned Highly Specialised Service (HSS) for Neuromuscular Diseases (NHS England) Sanofi Genzyme; Sanofi-Aventis; Genzyme Corporation National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London MR/N010035/1 / MRC; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) M145 / Rosetrees Trust PTC MR/N010035/1 / Medical Research Council; UK Research & Innovation (UKRI); Medical Research Council UK (MRC); European Commission Sarepta Therapeutics MRC/N010035/1 / Medical Research Council; UK Research & Innovation (UKRI); Medical Research Council UK (MRC); European Commission AVI BioPharma NF-SI-0515-10022 / National Institute for Health Research; National Institute for Health Research (NIHR) GlaxoSmithKline Trophos ZIANS003129 / NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) 512315 / Muscular Dystrophy UK RA4/924 / Muscular Dystrophy UK Friedrich-Baur-Stiftung 105616/Z/14/Z / Wellcome Trust Institutional Strategic Support Fund; Wellcome Trust Medical Research Council; UK Research & Innovation (UKRI); Medical Research Council UK (MRC); European Commission 305444; 305121 / European Union Seventh Framework Programme; European Commission
- Language
- English
- Date published
- 03/02/2017
- Academic Unit
- Pathology
- Record Identifier
- 9984276456102771
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