期刊
AMERICAN JOURNAL OF HUMAN GENETICS
卷 100, 期 3, 页码 523-536出版社
CELL PRESS
DOI: 10.1016/j.ajhg.2017.01.024
关键词
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资金
- Friedrich-Baur-Stiftung
- Wellcome Trust Institutional Strategic Support Fund [105616/Z/14/Z]
- Medical Research Council [MRC/N010035/1]
- National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London
- European Union Seventh Framework Programme [305444, 305121]
- Muscular Dystrophy UK [512315]
- Medical Research Council
- Nationally Commissioned Highly Specialised Service (HSS) for Neuromuscular Diseases (NHS England)
- Sanofi Genzyme
- Trophos
- GlaxoSmithKline
- AVI BioPharma
- PTC
- Sarepta Therapeutics
- Wellcome Trust [105616/Z/14/Z] Funding Source: Wellcome Trust
- MRC [MR/N010035/1] Funding Source: UKRI
- Medical Research Council [MR/N010035/1] Funding Source: researchfish
- Muscular Dystrophy UK [RA4/0924, RA4/924] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0515-10022] Funding Source: researchfish
- Rosetrees Trust [M145] Funding Source: researchfish
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.
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