Homozygous mutations in caveolin-3 cause a severe form of rippling muscle disease.
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.
Kubisch
Christian
C
Institute of Human Genetics, University of Bonn, Bonn, Germany.
Schoser
Benedikt G H
BG
von Düring
Monika
M
Betz
Regina C
RC
Goebel
Hans-Hilmar
HH
Zahn
Susanne
S
Ehrbrecht
Antje
A
Aasly
Jan
J
Schroers
Anja
A
Popovic
Nikola
N
Lochmüller
Hanns
H
Schröder
J Michael
JM
Brüning
Thomas
T
Malin
Jean-Pierre
JP
Fricke
Britta
B
Meinck
Hans-Michael
HM
Torbergsen
Torberg
T
Engels
Hartmut
H
Voss
Bruno
B
Vorgerd
Matthias
M
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
D051244:Caveolin 3; D022461:Caveolins; C114839:DYSF protein, human; D000073939:Dysferlin; D008565:Membrane Proteins; D009124:Muscle Proteins; D009252:NADPH Dehydrogenase