Dissociation of the dystroglycan complex in caveolin-3-deficient limb girdle muscular dystrophy

Limb girdle muscular dystrophy is a group of clinically and genetically heterogeneous disorders inherited in an autosomal recessive or dominant mode. Caveolin-3, the muscle-specific member of the caveolin gene family, is implicated in the pathogenesis of autosomal dominant limb girdle muscular dystr...

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Published in:	Human molecular genetics Vol. 9; no. 15; pp. 2335 - 2340
Main Authors:	HERRMANN, Ralf, STRAUB, Volker, BLANK, Martina, KUTZICK, Christian, FRANKE, Nicola, JACOB, Eva Neuen, LENARD, Hans-Gerd, KRÖGER, Stephan, VOIT, Thomas
Format:	Journal Article
Language:	English
Published:	Oxford Oxford University Press 22-09-2000 Oxford Publishing Limited (England)
Subjects:	Amino Acid Substitution Animals Biological and medical sciences Blotting, Western Caveolin 3 Caveolins - analysis Caveolins - genetics Caveolins - metabolism Child, Preschool Cytoskeletal Proteins - metabolism Diseases of striated muscles. Neuromuscular diseases DNA Mutational Analysis dystroglycan Dystroglycans Female Humans Immunohistochemistry limb-girdle muscular dystrophy Medical sciences Membrane Glycoproteins - metabolism Mice Muscle Proteins - analysis Muscle Proteins - genetics Muscle Proteins - metabolism Muscular Dystrophies - genetics Muscular Dystrophies - metabolism Muscular Dystrophies - pathology Mutation, Missense Neurology Nitric Oxide Synthase - metabolism Pedigree Polymerase Chain Reaction Polymorphism, Single-Stranded Conformational Human Neuromuscular diseases Nervous system diseases Enzyme Pathogenesis Gene expression Nitric-oxide synthase Genetic disease Case study Gene Limb girdle muscular dystrophy Oxidoreductases Mutation
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Summary:	Limb girdle muscular dystrophy is a group of clinically and genetically heterogeneous disorders inherited in an autosomal recessive or dominant mode. Caveolin-3, the muscle-specific member of the caveolin gene family, is implicated in the pathogenesis of autosomal dominant limb girdle muscular dystrophy 1C. Here we report on a 4-year-old girl presenting with myalgia and muscle cramps due to a caveolin-3 deficiency in her dystrophic skeletal muscle as a result of a heterozygous 136G-->A substitution in the caveolin-3 gene. The novel sporadic missense mutation in the caveolin signature sequence of the caveolin-3 gene changes an alanine to a threonine (A46T) and prevents the localization of caveolin-3 to the plasma membrane in a dominant negative fashion. Caveolin-3 has been suggested to interact with the dystrophin-glycoprotein complex, which in striated muscle fibers links the cytoskeleton to the extracellular matrix and with neuronal nitric oxide synthase. Similar to dystrophin-deficient Duchenne muscular dystrophy, a secondary decrease in neuronal nitric oxide synthase and alpha-dystroglycan expression was detected in the caveolin-3-deficient patient. These results implicate an important function of the caveolin signature sequence and common mechanisms in the pathogenesis of dystrophin-glycoprotein complex-associated muscular dystrophies with caveolin-3-deficient limb girdle muscular dystrophy.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	0964-6906 1460-2083
DOI:	10.1093/oxfordjournals.hmg.a018926