Identification and functional analysis of a caveolin-3 mutation associated with familial hypertrophic cardiomyopathy

Hayashi, Takeharu; Arimura, Takuro; Ueda, Kazuo; Shibata, Hiroki; Hohda, Shigeru; Takahashi, Megumi; Hori, Hisae; Koga, Yoshinori; Oka, Naoki; Imaizumi, Tsutomu; Yasunami, Michio; Kimura, Akinori

doi:10.1016/j.bbrc.2003.11.101

Cited by 146 publications

(104 citation statements)

References 29 publications

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“…It could also be possible that our patient's cardiomyopathy was not primarily dilatative but represented the late clinical course of a hypertrophic condition. This would be in agreement with the description by Hayashi et al, 31 who reported the occurrence of HCM in two brothers affected by a CAV3 missense variant.…”

Section: Discussionsupporting

confidence: 94%

“…On the one hand, as mentioned earlier, one study describes the occurrence of HCM in two brothers carrying a CAV3 T63S substitution. 31 On the other hand, Cav-3 expression and caveolar structures 2) and an age-matched control (Control) were prepared and immunostained with specific antibodies against caveolin-3 (Cav-3) and dysferlin (Dysf). In control muscle, Cav-3 and Dysf display a uniform pattern at the sarcolemma.…”

Section: Discussionmentioning

confidence: 99%

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Caveolin-3 T78M and T78K missense mutations lead to different phenotypes in vivo and in vitro

Traverso

Gazzerro

Assereto

et al. 2008

Laboratory Investigation

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Caveolins are the principal protein components of caveolae, invaginations of the plasma membrane involved in cell signaling and trafficking. Caveolin-3 (Cav-3) is the muscle-specific isoform of the caveolin family and mutations in the CAV3 gene lead to a large group of neuromuscular disorders. In unrelated patients, we identified two distinct CAV3 mutations involving the same codon 78. Patient 1, affected by dilated cardiomyopathy and limb girdle muscular dystrophy (LGMD)-1C, shows an autosomal recessive mutation converting threonine to methionine (T78M). Patient 2, affected by isolated familiar hyperCKemia, shows an autosomal dominant mutation converting threonine to lysine (T78K). Cav-3 wild type (WT) and Cav-3 mutations were transiently transfected into Cos-7 cells. Cav-3 WT and Cav-3 T78M mutant localized at the plasma membrane, whereas Cav-3 T78K was retained in a perinuclear compartment. Cav-3 T78K expression was decreased by 87% when compared with Cav-3 WT, whereas Cav-3 T78M protein levels were unchanged. To evaluate whether Cav-3 T78K and Cav-3 T78M mutants behaved with a dominant negative pattern, Cos-7 cells were cotransfected with green fluorescent protein (GFP)-Cav-3 WT in combination with either mutant or WT Cav-3. When cotransfected with Cav-3 WT or Cav-3 T78M, GFP-Cav-3 WT was localized at the plasma membrane, as expected. However, when cotransfected with Cav-3 T78K, GFP-Cav-3 WT was retained in a perinuclear compartment, and its protein levels were reduced by 60%, suggesting a dominant negative action. Accordingly, Cav-3 protein levels in muscles from a biopsy of patient 2 (T78K mutation) were reduced by 80%. In conclusion, CAV3 T78M and T78K mutations lead to distinct disorders showing different clinical features and inheritance, and displaying distinct phenotypes in vitro.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Caveolin-3 T78M and T78K missense mutations lead to different phenotypes in vivo and in vitro

Traverso

Gazzerro

Assereto

et al. 2008

Laboratory Investigation

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show abstract

“…48 For example, the CAV3 mutation p.T63S found in a case of HCM is analogous to mutations [p.T63P and p.TFT (63)(64)(65)] identified in association with LGMD-1C. 54,77 Similarly, the same p.R26Q CAV3 mutation was reported in a family with extreme phenotypic variability. Of the 11 individuals with the confirmed mutation, three exhibited both RMD and LGMD-1C features, two had predominantly LGMD1C characteristics, two, both minors, had muscle stiffness only, and one was asymptomatic.…”

Section: Caveolin-3 and Muscle Diseasesmentioning

confidence: 62%

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

et al. 2009

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“…Recent discoveries have implicated several genes encoding components of the Z-disc as well as genes previously associated with dilated cardiomyopathy in the pathogenesis of HCM [19,31,32]. This paper reports the discovery of S101R, Y141H, and S165F mutations in JPH2 as a novel genetic basis for HCM.…”

Section: Discussionmentioning

confidence: 85%

Mutations in JPH2-encoded junctophilin-2 associated with hypertrophic cardiomyopathy in humans

Landstrom

Weisleder

Batalden

et al. 2007

Journal of Molecular and Cellular Cardiology

165

163

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Identification and functional analysis of a caveolin-3 mutation associated with familial hypertrophic cardiomyopathy

Cited by 146 publications

References 29 publications

Caveolin-3 T78M and T78K missense mutations lead to different phenotypes in vivo and in vitro

Caveolin-3 T78M and T78K missense mutations lead to different phenotypes in vivo and in vitro

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

Mutations in JPH2-encoded junctophilin-2 associated with hypertrophic cardiomyopathy in humans

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