Homozygous mutations in caveolin-3 cause a severe form of rippling muscle disease

• Published in: Annals of neurology Vol. 53; no. 4; pp. 512 - 520
• Main Authors: Kubisch, Christian, Schoser, Benedikt G. H., Düring, Monika v., Betz, Regina C., Goebel, Hans-Hilmar, Zahn, Susanne, Ehrbrecht, Antje, Aasly, Jan, Schroers, Anja, Popovic, Nikola, Lochmüller, Hanns, Schröder, J. Michael, Brüning, Thomas, Malin, Jean-Pierre, Fricke, Britta, Meinck, Hans-Michael, Torbergsen, Torberg, Engels, Hartmut, Voss, Bruno, Vorgerd, Matthias
• Format: Journal Article
• Language: English
• Published: New York Wiley Subscription Services, Inc., A Wiley Company 01.04.2003; Willey-Liss
• Subjects: Adult; Biological and medical sciences; Caveolin 3; Caveolins - genetics; Caveolins - metabolism; Diseases of striated muscles. Neuromuscular diseases; Dysferlin; Genotype; Homozygote; Humans; Male; Medical sciences; Membrane Proteins; Microscopy, Electron; Muscle Fibers, Skeletal - pathology; Muscle Fibers, Skeletal - ultrastructure; Muscle Proteins - metabolism; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Muscular Diseases - genetics; Muscular Diseases - metabolism; Muscular Diseases - pathology; Mutation, Missense; NADPH Dehydrogenase - metabolism; Neurology; Phenotype; Severity of Illness Index; Human; Immunohistochemistry; Genotype; Male; Homozygosity; Electron microscopy; Genetic determinism; Genetic disease; Case study; Pathology; Striated muscle disease; Phenotype; Ultrastructure; Adult; Female; Mutation
• ISSN: 0364-5134; 1531-8249
• DOI: 10.1002/ana.10501

Heterozygous missense mutations in the caveolin‐3 gene (CAV3) cause different muscle disorders. Most patients with CAV3 alterations present with rippling muscle disease (RMD) characterized by signs of increased muscle irritability without muscle weakness. In some patients, CAV3 mutations underlie the progressive limb‐girdle muscular dystrophy type 1C (LGMD1C). Here, we report two unrelated patients with novel homozygous mutations (L86P and A92T) in CAV3. Both presented with a more severe clinical phenotype than usually seen in RMD. Immunohistochemical and immunoblot analyses of muscle biopsies showed a strong reduction of caveolin‐3 in both homozygous RMD patients similar to the findings in heterozygous RMD. Electron microscopy studies showed a nearly complete absence of caveolae in the sarcolemma in all RMD patients analyzed. Additional plasma membrane irregularities (small plasmalemmal discontinuities, subsarcolemmal vacuoles, abnormal papillary projections) were more pronounced in homozygous than in heterozygous RMD patients. A stronger activation of nitric oxide synthase was observed in both homozygous patients compared with heterozygous RMD. Like in LGMD1C, dysferlin immunoreactivity is reduced in RMD but more pronounced in homozygous as compared with heterozygous RMD. Thus, we further extend the phenotypic variability of muscle caveolinopathies by identification of a severe form of RMD associated with homozygous CAV3 mutations. Ann Neurol 2003