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 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.
Herrmann
R
R
Department of Pediatrics and Pediatric Neurology, University of Essen, Hufelandstrasse 55, 45122 Essen, Germany.
Straub
V
V
Blank
M
M
Kutzick
C
C
Franke
N
N
Jacob
E N
EN
Lenard
H G
HG
Kröger
S
S
Voit
T
T
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
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