title: Dissociation of the dystroglycan complex in caveolin-3-deficient limb girdle muscular dystrophy.
abstract: 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.
authors.affiliation: Department of Pediatrics and Pediatric Neurology, University of Essen, Hufelandstrasse 55, 45122 Essen, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Herrmann
authors.forename: V
authors.initials: V
authors.lastname: Straub
authors.forename: M
authors.initials: M
authors.lastname: Blank
authors.forename: C
authors.initials: C
authors.lastname: Kutzick
authors.forename: N
authors.initials: N
authors.lastname: Franke
authors.forename: E N
authors.initials: EN
authors.lastname: Jacob
authors.forename: H G
authors.initials: HG
authors.lastname: Lenard
authors.forename: S
authors.initials: S
authors.lastname: Kröger
authors.forename: T
authors.initials: T
authors.lastname: Voit
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D015153:Blotting, Western; D051244:Caveolin 3; D022461:Caveolins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D002675:Child, Preschool; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004252:DNA Mutational Analysis; D049030:Dystroglycans; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D009124:Muscle Proteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D009136:Muscular Dystrophies / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020125:Mutation, Missense; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010375:Pedigree; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational
chemical_list: C495548:Cav3 protein, mouse; D051244:Caveolin 3; D022461:Caveolins; D003598:Cytoskeletal Proteins; C483081:DAG1 protein, human; D008562:Membrane Glycoproteins; D009124:Muscle Proteins; D049030:Dystroglycans; D019001:Nitric Oxide Synthase