Mutations in the area composita protein αT-catenin are associated with arrhythmogenic right ventricular cardiomyopathy.
Eur Heart J
; 34(3): 201-10, 2013 Jan.
Article
em En
| MEDLINE
| ID: mdl-23136403
ABSTRACT
AIMS:
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a major cause of juvenile sudden death and is characterized by fibro-fatty replacement of the right ventricle. Mutations in several genes encoding desmosomal proteins have been identified in ARVC. We speculated that αT-catenin, encoded by CTNNA3, might also carry mutations in ARVC patients. Alpha-T-catenin binds plakophilins and this binding contributes to the formation of the area composita, which strengthens cell-cell adhesion in contractile cardiomyocytes. METHODS ANDRESULTS:
We used denaturing high-performance liquid chromatography and direct sequencing to screen CTNNA3 in 76 ARVC patients who did not carry any mutations in the desmosomal genes commonly mutated in ARVC. Mutations c.281T > A (p.V94D) and c.2293_2295delTTG (p.del765L) were identified in two probands. They are located in important domains of αT-catenin. Yeast two-hybrid and cell transfection studies showed that the interaction between the p.V94D mutant protein and ß-catenin was affected, whereas the p.del765L mutant protein showed a much stronger dimerization potential and formed aggresomes in HEK293T cells.CONCLUSION:
These findings might point to a causal relationship between CTNNA3 mutations and ARVC. This first report on the involvement of an area composita gene in ARVC shows that the pathogenesis of this disease extends beyond desmosomes. Since the frequency of CTNNA3 mutations in ARVC patients is not rare, systematic screening for this gene should be considered to improve the clinical management of ARVC families.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Morte Súbita Cardíaca
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Deleção de Genes
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Displasia Arritmogênica Ventricular Direita
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Mutação de Sentido Incorreto
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Alfa Catenina
Tipo de estudo:
Observational_studies
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Prognostic_studies
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Risk_factors_studies
Limite:
Adult
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Female
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Humans
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Male
Idioma:
En
Revista:
Eur Heart J
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Bélgica