title: Homozygous mutations in caveolin-3 cause a severe form of rippling muscle disease.
abstract: 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.
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Kubisch
authors.forename: Benedikt G H
authors.initials: BG
authors.lastname: Schoser
authors.forename: Monika
authors.initials: M
authors.lastname: von Düring
authors.forename: Regina C
authors.initials: RC
authors.lastname: Betz
authors.forename: Hans-Hilmar
authors.initials: HH
authors.lastname: Goebel
authors.forename: Susanne
authors.initials: S
authors.lastname: Zahn
authors.forename: Antje
authors.initials: A
authors.lastname: Ehrbrecht
authors.forename: Jan
authors.initials: J
authors.lastname: Aasly
authors.forename: Anja
authors.initials: A
authors.lastname: Schroers
authors.forename: Nikola
authors.initials: N
authors.lastname: Popovic
authors.forename: Hanns
authors.initials: H
authors.lastname: Lochmüller
authors.forename: J Michael
authors.initials: JM
authors.lastname: Schröder
authors.forename: Thomas
authors.initials: T
authors.lastname: Brüning
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Malin
authors.forename: Britta
authors.initials: B
authors.lastname: Fricke
authors.forename: Hans-Michael
authors.initials: HM
authors.lastname: Meinck
authors.forename: Torberg
authors.initials: T
authors.lastname: Torbergsen
authors.forename: Hartmut
authors.initials: H
authors.lastname: Engels
authors.forename: Bruno
authors.initials: B
authors.lastname: Voss
authors.forename: Matthias
authors.initials: M
authors.lastname: Vorgerd
mesh_terms: D000328:Adult; D051244:Caveolin 3; D022461:Caveolins / Q000235:genetics* / Q000378:metabolism; D000073939:Dysferlin; D005838:Genotype; D006720:Homozygote; D006801:Humans; D008297:Male; D008565:Membrane Proteins; D008854:Microscopy, Electron; D018485:Muscle Fibers, Skeletal / Q000473:pathology / Q000648:ultrastructure; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009135:Muscular Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020125:Mutation, Missense; D009252:NADPH Dehydrogenase / Q000378:metabolism; D010641:Phenotype; D012720:Severity of Illness Index
chemical_list: D051244:Caveolin 3; D022461:Caveolins; C114839:DYSF protein, human; D000073939:Dysferlin; D008565:Membrane Proteins; D009124:Muscle Proteins; D009252:NADPH Dehydrogenase