Author(s): Straub V; Herrmann R; Blank M; Kutzick C; Franke N; Jacob EN; Lenard HG; Kroger S; Voit T
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.
Keywords: Amino Acid Substitution Animals Blotting, Western Caveolin 3 Caveolins/analysis/ genetics/metabolism Child, Preschool Cytoskeletal Proteins/ metabolism DNA Mutational Analysis Dystroglycans Female Humans Immunohistochemistry Membrane Glycoproteins/ metabolism Mice Muscle Proteins/analysis/ genetics/metabolism Muscular Dystrophies/ genetics/metabolism/pathology Mutation, Missense Nitric Oxide Synthase/metabolism Pedigree Polymerase Chain Reaction Polymorphism, Single-Stranded Conformational