期刊
NEW ENGLAND JOURNAL OF MEDICINE
卷 364, 期 10, 页码 939-946出版社
MASSACHUSETTS MEDICAL SOC
DOI: 10.1056/NEJMoa1006939
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资金
- Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center [1U54NS053672]
- Hacettepe University Research Fund [03.02.101.009, SBAG-1774]
- National Institutes of Health [AI45927]
- National Institute of Diabetes and Digestive and Kidney Diseases [P30 DK 54759]
- Muscular Dystrophy Campaign and Institute of Child Health Biomedical Research Centre
- MRC [G0601943] Funding Source: UKRI
- Medical Research Council [G0601943] Funding Source: researchfish
Dystroglycan, which serves as a major extracellular matrix receptor in muscle and the central nervous system, requires extensive O-glycosylation to function. We identified a dystroglycan missense mutation (Thr192. Met) in a woman with limb-girdle muscular dystrophy and cognitive impairment. A mouse model harboring this mutation recapitulates the immunohistochemical and neuromuscular abnormalities observed in the patient. In vitro and in vivo studies showed that the mutation impairs the receptor function of dystroglycan in skeletal muscle and brain by inhibiting the post-translational modification, mediated by the glycosyltransferase LARGE, of the phosphorylated O-mannosyl glycans on a-dystroglycan that is required for high-affinity binding to laminin.
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