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.

Caveolinopathies: from the biology of caveolin-3 to human diseases

“…8,9 Cav-3 and dystrophin competitively bind to the same site of b-dystroglycan and changes in Cav-3 expression as in Cav-3 transgenics lead to the disruption of the DGC and to downregulation of dystrophin protein levels. [10][11][12][13] Muscle caveolae are implied also in the regulation of different signaling pathways. Indeed, signaling molecules such as Gi2a, Gbg, c-Src, Src kinases, GPI-linked proteins, nitric oxide synthases (neuronal and inducible NOS) and type I myostatin receptors display a specific caveolin-binding domain motif which interacts with Cav-3 scaffolding segment.…”

“…12,44,[55][56][57][58] In LGMD-1C patients, electromyographic studies range from a normal to a myopathic pattern, whereas muscle biopsy analysis can show variably sized, degenerating/regenerating muscle fibers, with an increased number of central nuclei, and a mild substitution of connective tissue. The expression of Cav-3 is reduced invariably both by immunohistochemistry and immunoblot analysis in muscle fibers.…”

Caveolin-1/3 Double-Knockout Mice Are Viable, but Lack Both Muscle and Non-Muscle Caveolae, and Develop a Severe Cardiomyopathic Phenotype

“…Mutations within the Cav-3 gene (P104L; ⌬TFT 63-65; A45T) result in LGMD-1C. 18,49 Given that there is a greater than 90% reduction in the expression of Cav-3 within the skeletal muscles of patients with LGMD-1C, the Cav-3 KO mouse has served as a model system for this disease process. Interestingly, the T-tubule system within both the Cav-3 KO mouse and human LGMD-1C skeletal muscles is structurally defective, thus suggesting possible functional derangements in this important membrane system.…”

A POGLUT1 mutation causes a muscular dystrophy with reduced notch signaling and satellite cell loss

“…The anti-a-dystroglycan core protein (a kind donation from S. Kröger) sheep polyclonal antibody was raised against a synthetic peptide corresponding to the carboxy-terminal 20 amino acids of chick a-dystroglycan (Herrmann et al, 2000).…”