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A dystroglycan mutation associated with limb-girdle muscular dystrophy.

TitleA dystroglycan mutation associated with limb-girdle muscular dystrophy.
Publication TypeJournal Article
Year of Publication2011
AuthorsHara Y, Balci-Hayta B, Yoshida-Moriguchi T, Kanagawa M, de Bernabé DBeltrán-V, Gündeşli H, Willer T, Satz JS, Crawford RW, Burden SJ, Kunz S, Oldstone MBA, Accardi A, Talim B, Muntoni F, Topaloğlu H, Dinçer P, Campbell KP
JournalN Engl J Med
Volume364
Issue10
Pagination939-46
Date Published2011 Mar 10
ISSN1533-4406
KeywordsAnimals, Disease Models, Animal, Dystroglycans, Female, Humans, Mice, Muscular Dystrophies, Limb-Girdle, Mutation, Missense, Pedigree, Phenotype, Sequence Analysis, DNA
Abstract

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 α-dystroglycan that is required for high-affinity binding to laminin.

DOI10.1056/NEJMoa1006939
Alternate JournalN. Engl. J. Med.
PubMed ID21388311
PubMed Central IDPMC3071687
Grant List1U54NS053672 / NS / NINDS NIH HHS / United States
AI45927 / AI / NIAID NIH HHS / United States
G0502130 / / Medical Research Council / United Kingdom
G0601943 / / Medical Research Council / United Kingdom
P30 DK 54759 / DK / NIDDK NIH HHS / United States
P30 DK054759 / DK / NIDDK NIH HHS / United States
P30 DK054759-11 / DK / NIDDK NIH HHS / United States
R01 AI009484 / AI / NIAID NIH HHS / United States
R01 AI045927 / AI / NIAID NIH HHS / United States
R01 AI045927-10 / AI / NIAID NIH HHS / United States
R01 DK051315 / DK / NIDDK NIH HHS / United States
R01 GM085232 / GM / NIGMS NIH HHS / United States
U54 NS053672 / NS / NINDS NIH HHS / United States
U54 NS053672-07 / NS / NINDS NIH HHS / United States
/ / Howard Hughes Medical Institute / United States

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