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Limb-girdle muscular dystrophies - From genetics to molecular pathology

Lookup NU author(s): Dr Steven Laval, Emerita Professor Katherine Bushby

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Abstract

The limb-girdle muscular dystrophies are a diverse group of muscle-wasting disorders characteristically affecting the large muscles of the pelvic and shoulder girdles. Molecular genetic analyses have demonstrated causative mutations in the genes encoding a disparate collection of proteins involved in all aspects of muscle cell biology. Muscular dystrophy includes a spectrum of disorders caused by loss of the linkage between the extracellular matrix and the actin cytoskeleton. Within this are the forms of limb-girdle muscular dystrophy caused by deficiencies of the sarcoglycan complex and by aberrant glycosylation of α-dystroglycan caused by mutations in the fukutin-related protein gene. However, other forms of this disease have distinct pathophysiological mechanisms. For example, deficiency of dysferlin disrupts sarcolemmal membrane repair, whilst loss of calpain-3 may exert its pathological influence either by perturbation of the IκBα/NF-κB pathway, or through calpain-dependent cytoskeletal remodelling. Caveolin-3 is implicated in numerous cell-signalling pathways and involved in the biogenesis of the T-tubule system. Alterations in the nuclear lamina caused by mutations in laminA/C, sarcomeric changes in titin, telethonin or myotilin at the Z-disc, and subtle changes in the extracellular matrix proteins laminin-α2 or collagen VI can all lead to a limb-girdle muscular dystrophy phenotype, although the specific pathological mechanisms remain obscure. Differential diagnosis of these disorders requires the careful application of a broad range of disciplines: clinical assessment, immunohistochemistry and immunoblotting using a panel of antibodies and extensive molecular genetic analyses.

Publication metadata

Author(s): Laval SH, Bushby KMD

Publication type: Article

Publication status: Published

Journal: Neuropathology and Applied Neurobiology

Year: 2004

Volume: 30

Issue: 2

Pages: 91-105

ISSN (print): 0305-1846

ISSN (electronic): 1365-2990

Publisher: Wiley-Blackwell

URL: http://dx.doi.org/10.1111/j.1365-2990.2004.00555.x

DOI: 10.1111/j.1365-2990.2004.00555.x

PubMed id: 15043707

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