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Mutations in the area composita protein T-catenin are associated with arrhythmogenic right ventricular cardiomyopathy

(2013) EUROPEAN HEART JOURNAL. 34(3). p.201-210
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Abstract
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 T-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 cellcell adhesion in contractile cardiomyocytes. 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 T-catenin. Yeast two-hybrid and cell transfection studies showed that the interaction between the p.V94D mutant protein and -catenin was affected, whereas the p.del765L mutant protein showed a much stronger dimerization potential and formed aggresomes in HEK293T cells. 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.
Keywords
Sudden cardiac death, Arrhythmia, WOOLLY HAIR, E-CADHERIN, DYSPLASIA, NAXOS-DISEASE, BETA-CATENIN, DILATED CARDIOMYOPATHY, ADHERING JUNCTIONS, PLAKOGLOBIN CAUSES, CELL-CELL ADHESION, ALPHA-CATENIN, Genetics, Cell adhesion molecules, Cardiomyopathy

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Citation

Please use this url to cite or link to this publication:

Chicago
van Hengel, Jolanda, Martina Calore, Barbara Bauce, Emanuela Dazzo, Elisa Mazzotti, Marzia De Bortoli, Alessandra Lorenzon, et al. 2013. “Mutations in the Area Composita Protein T-catenin Are Associated with Arrhythmogenic Right Ventricular Cardiomyopathy.” European Heart Journal 34 (3): 201–210.
APA
van Hengel, J., Calore, M., Bauce, B., Dazzo, E., Mazzotti, E., De Bortoli, M., Lorenzon, A., et al. (2013). Mutations in the area composita protein T-catenin are associated with arrhythmogenic right ventricular cardiomyopathy. EUROPEAN HEART JOURNAL, 34(3), 201–210.
Vancouver
1.
van Hengel J, Calore M, Bauce B, Dazzo E, Mazzotti E, De Bortoli M, et al. Mutations in the area composita protein T-catenin are associated with arrhythmogenic right ventricular cardiomyopathy. EUROPEAN HEART JOURNAL. 2013;34(3):201–10.
MLA
van Hengel, Jolanda, Martina Calore, Barbara Bauce, et al. “Mutations in the Area Composita Protein T-catenin Are Associated with Arrhythmogenic Right Ventricular Cardiomyopathy.” EUROPEAN HEART JOURNAL 34.3 (2013): 201–210. Print.
@article{3137754,
  abstract     = {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 T-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 cellcell adhesion in contractile cardiomyocytes.
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 T-catenin. Yeast two-hybrid and cell transfection studies showed that the interaction between the p.V94D mutant protein and -catenin was affected, whereas the p.del765L mutant protein showed a much stronger dimerization potential and formed aggresomes in HEK293T cells.
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.},
  author       = {van Hengel, Jolanda and Calore, Martina and Bauce, Barbara and Dazzo, Emanuela and Mazzotti, Elisa and De Bortoli, Marzia and Lorenzon, Alessandra and Li Mura, Ilena EA and Beffagna, Giorgia and Rigato, Ilaria and Vleeschouwers, Mara and Tyberghein, Koen and Hulpiau, Paco and Van Hamme, Evelien and Zaglia, Tania and Corrado, Domenico and Basso, Cristina and Thiene, Gaetano and Daliento, Luciano and Nava, Andrea and Van Roy, Frans and Rampazzo, Alessandra},
  issn         = {0195-668X},
  journal      = {EUROPEAN HEART JOURNAL},
  keywords     = {Sudden cardiac death,Arrhythmia,WOOLLY HAIR,E-CADHERIN,DYSPLASIA,NAXOS-DISEASE,BETA-CATENIN,DILATED CARDIOMYOPATHY,ADHERING JUNCTIONS,PLAKOGLOBIN CAUSES,CELL-CELL ADHESION,ALPHA-CATENIN,Genetics,Cell adhesion molecules,Cardiomyopathy},
  language     = {eng},
  number       = {3},
  pages        = {201--210},
  title        = {Mutations in the area composita protein T-catenin are associated with arrhythmogenic right ventricular cardiomyopathy},
  url          = {http://dx.doi.org/10.1093/eurheartj/ehs373},
  volume       = {34},
  year         = {2013},
}

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