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Abnormalities in alpha-Dystroglycan Expression in MDC1C and LGMD21 Muscular Dystrophies

Lookup NU author(s): Dr Louise VB Anderson, Emerita Professor Katherine Bushby

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Abstract

We recently identified mutations in the fukutin related protein (FKRP) gene in patients with congenital muscular dystrophy type 1C (MDC1C) and limb girdle muscular dystrophy type 21 (LGMD21). The sarcolemma of these patients typically displays an immunocytochemical reduction of alpha-dystroglycan. in this report we extend these observations and report a clear correlation between the residual expression of alpha-dystroglycan and the phenotype. Three broad categories were identified. Patients at the severe end of the clinical spectrum (MDC1C) were compound heterozygote between a null allele and a missense mutation or carried two missense mutations and displayed a profound depletion of alpha-dystroglycan. Patients with LGMD with a Duchenne-like severity typically had a moderate reduction in alpha-dystroglycan and were compound heterozygotes; between a common C826A (Lcu276Ileu) FKRP mutation and either a missense or a nonsense mutation. Individuals with the milder form of LGMD21 were almost invariably homozygous for the Leu276Ile FKRP mutation and showed a variable but subtle alteration in alpha-dystroglycan immunolabeling. Our data therefore suggest a correlation between a reduction in alpha-dystroglycan, the mutation and the clinical phenotype in MDC1C and LGMD21 which supports the hypothesis that dystroglycan plays a central role in the pathogenesis of these disorders.


Publication metadata

Author(s): Brown SC, Torelli S, Brockington M, Yuva Y, Jimenez C, Feng L, Anderson L, Ugo I, Kroger S, Bushby K, Voit T, Sewry C, Muntoni F

Publication type: Article

Publication status: Published

Journal: American Journal of Pathology

Year: 2004

Volume: 164

Issue: 2

Pages: 727-737

ISSN (print): 0002-9440

ISSN (electronic): 1525-2191

Publisher: American Society for Investigative Pathology

URL: http://ajp.amjpathol.org/cgi/reprint/164/2/727


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