Mutations in desmoglein-2 gene are associated with arrhythmogenic right ventricular cardiomyopathy

Kalliopi Pilichou, Andrea Nava, Cristina Basso, Giorgia Beffagna, Barbara Bauce, Alessandra Lorenzon, Gianfranco Frigo, Andrea Vettori, Marialuisa Valente, Jeffrey Towbin, Gaetano Thiene, Gian Antonio Danieli, Alessandra Rampazzo

Research output: Contribution to journalArticle

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Abstract

Background - Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by progressive myocardial atrophy with fibrofatty replacement. The recent identification of causative mutations in plakoglobin, desmoplakin (DSP), and plakophilin-2 (PKP2) genes led to the hypothesis that ARVC is due to desmosomal defects. Therefore, desmoglein-2 (DSG2), the only desmoglein isoform expressed in cardiac myocytes, was screened in subjects with ARVC. Methods and Results - In a series of 80 unrelated ARVC probands, 26 carried a mutation in DSP (16%), PKP2 (14%), and transforming growth factor-β3 (2.5%) genes; the remaining 54 were screened for DSG2 mutations by denaturing high-performance liquid chromatography and direct sequencing. Nine heterozygous DSG2 mutations (5 missense, 2 insertion-deletions, 1 nonsense, and 1 splice site mutation) were detected in 8 probands (10%). All probands fulfilled task force criteria for ARVC. An endomyocardial biopsy was obtained in 5, showing extensive loss of myocytes with fibrofatty tissue replacement. In 3 patients, electron microscopy investigation was performed, showing intercalated disc paleness, decreased desmosome number, and intercellular gap widening. Conclusions - This is the first investigation demonstrating DSG2 gene mutations in a significant number of ARVC-unrelated probands. Cardiac phenotype is characterized clinically by typical ARVC features with frequent left ventricular involvement and morphologically by fibrofatty myocardial replacement and desmosomal remodeling. The presence of mutations in desmosomal encoding genes in 40% of cases confirms that many forms of ARVC are due to alterations in the desmosome complex.

Original languageEnglish (US)
Pages (from-to)1171-1179
Number of pages9
JournalCirculation
Volume113
Issue number9
DOIs
StatePublished - Mar 1 2006
Externally publishedYes

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Desmoglein 2
Arrhythmogenic Right Ventricular Dysplasia
Mutation
Genes
Plakophilins
Desmoplakins
Desmosomes
Desmogleins
gamma Catenin
Transforming Growth Factors
Advisory Committees
Missense Mutation
Cardiomyopathies
Cardiac Myocytes
Muscle Cells
Atrophy
Electron Microscopy
Protein Isoforms
High Pressure Liquid Chromatography

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Pilichou, K., Nava, A., Basso, C., Beffagna, G., Bauce, B., Lorenzon, A., ... Rampazzo, A. (2006). Mutations in desmoglein-2 gene are associated with arrhythmogenic right ventricular cardiomyopathy. Circulation, 113(9), 1171-1179. https://doi.org/10.1161/CIRCULATIONAHA.105.583674

Mutations in desmoglein-2 gene are associated with arrhythmogenic right ventricular cardiomyopathy. / Pilichou, Kalliopi; Nava, Andrea; Basso, Cristina; Beffagna, Giorgia; Bauce, Barbara; Lorenzon, Alessandra; Frigo, Gianfranco; Vettori, Andrea; Valente, Marialuisa; Towbin, Jeffrey; Thiene, Gaetano; Danieli, Gian Antonio; Rampazzo, Alessandra.

In: Circulation, Vol. 113, No. 9, 01.03.2006, p. 1171-1179.

Research output: Contribution to journalArticle

Pilichou, K, Nava, A, Basso, C, Beffagna, G, Bauce, B, Lorenzon, A, Frigo, G, Vettori, A, Valente, M, Towbin, J, Thiene, G, Danieli, GA & Rampazzo, A 2006, 'Mutations in desmoglein-2 gene are associated with arrhythmogenic right ventricular cardiomyopathy', Circulation, vol. 113, no. 9, pp. 1171-1179. https://doi.org/10.1161/CIRCULATIONAHA.105.583674
Pilichou, Kalliopi ; Nava, Andrea ; Basso, Cristina ; Beffagna, Giorgia ; Bauce, Barbara ; Lorenzon, Alessandra ; Frigo, Gianfranco ; Vettori, Andrea ; Valente, Marialuisa ; Towbin, Jeffrey ; Thiene, Gaetano ; Danieli, Gian Antonio ; Rampazzo, Alessandra. / Mutations in desmoglein-2 gene are associated with arrhythmogenic right ventricular cardiomyopathy. In: Circulation. 2006 ; Vol. 113, No. 9. pp. 1171-1179.
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abstract = "Background - Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by progressive myocardial atrophy with fibrofatty replacement. The recent identification of causative mutations in plakoglobin, desmoplakin (DSP), and plakophilin-2 (PKP2) genes led to the hypothesis that ARVC is due to desmosomal defects. Therefore, desmoglein-2 (DSG2), the only desmoglein isoform expressed in cardiac myocytes, was screened in subjects with ARVC. Methods and Results - In a series of 80 unrelated ARVC probands, 26 carried a mutation in DSP (16{\%}), PKP2 (14{\%}), and transforming growth factor-β3 (2.5{\%}) genes; the remaining 54 were screened for DSG2 mutations by denaturing high-performance liquid chromatography and direct sequencing. Nine heterozygous DSG2 mutations (5 missense, 2 insertion-deletions, 1 nonsense, and 1 splice site mutation) were detected in 8 probands (10{\%}). All probands fulfilled task force criteria for ARVC. An endomyocardial biopsy was obtained in 5, showing extensive loss of myocytes with fibrofatty tissue replacement. In 3 patients, electron microscopy investigation was performed, showing intercalated disc paleness, decreased desmosome number, and intercellular gap widening. Conclusions - This is the first investigation demonstrating DSG2 gene mutations in a significant number of ARVC-unrelated probands. Cardiac phenotype is characterized clinically by typical ARVC features with frequent left ventricular involvement and morphologically by fibrofatty myocardial replacement and desmosomal remodeling. The presence of mutations in desmosomal encoding genes in 40{\%} of cases confirms that many forms of ARVC are due to alterations in the desmosome complex.",
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T1 - Mutations in desmoglein-2 gene are associated with arrhythmogenic right ventricular cardiomyopathy

AU - Pilichou, Kalliopi

AU - Nava, Andrea

AU - Basso, Cristina

AU - Beffagna, Giorgia

AU - Bauce, Barbara

AU - Lorenzon, Alessandra

AU - Frigo, Gianfranco

AU - Vettori, Andrea

AU - Valente, Marialuisa

AU - Towbin, Jeffrey

AU - Thiene, Gaetano

AU - Danieli, Gian Antonio

AU - Rampazzo, Alessandra

PY - 2006/3/1

Y1 - 2006/3/1

N2 - Background - Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by progressive myocardial atrophy with fibrofatty replacement. The recent identification of causative mutations in plakoglobin, desmoplakin (DSP), and plakophilin-2 (PKP2) genes led to the hypothesis that ARVC is due to desmosomal defects. Therefore, desmoglein-2 (DSG2), the only desmoglein isoform expressed in cardiac myocytes, was screened in subjects with ARVC. Methods and Results - In a series of 80 unrelated ARVC probands, 26 carried a mutation in DSP (16%), PKP2 (14%), and transforming growth factor-β3 (2.5%) genes; the remaining 54 were screened for DSG2 mutations by denaturing high-performance liquid chromatography and direct sequencing. Nine heterozygous DSG2 mutations (5 missense, 2 insertion-deletions, 1 nonsense, and 1 splice site mutation) were detected in 8 probands (10%). All probands fulfilled task force criteria for ARVC. An endomyocardial biopsy was obtained in 5, showing extensive loss of myocytes with fibrofatty tissue replacement. In 3 patients, electron microscopy investigation was performed, showing intercalated disc paleness, decreased desmosome number, and intercellular gap widening. Conclusions - This is the first investigation demonstrating DSG2 gene mutations in a significant number of ARVC-unrelated probands. Cardiac phenotype is characterized clinically by typical ARVC features with frequent left ventricular involvement and morphologically by fibrofatty myocardial replacement and desmosomal remodeling. The presence of mutations in desmosomal encoding genes in 40% of cases confirms that many forms of ARVC are due to alterations in the desmosome complex.

AB - Background - Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by progressive myocardial atrophy with fibrofatty replacement. The recent identification of causative mutations in plakoglobin, desmoplakin (DSP), and plakophilin-2 (PKP2) genes led to the hypothesis that ARVC is due to desmosomal defects. Therefore, desmoglein-2 (DSG2), the only desmoglein isoform expressed in cardiac myocytes, was screened in subjects with ARVC. Methods and Results - In a series of 80 unrelated ARVC probands, 26 carried a mutation in DSP (16%), PKP2 (14%), and transforming growth factor-β3 (2.5%) genes; the remaining 54 were screened for DSG2 mutations by denaturing high-performance liquid chromatography and direct sequencing. Nine heterozygous DSG2 mutations (5 missense, 2 insertion-deletions, 1 nonsense, and 1 splice site mutation) were detected in 8 probands (10%). All probands fulfilled task force criteria for ARVC. An endomyocardial biopsy was obtained in 5, showing extensive loss of myocytes with fibrofatty tissue replacement. In 3 patients, electron microscopy investigation was performed, showing intercalated disc paleness, decreased desmosome number, and intercellular gap widening. Conclusions - This is the first investigation demonstrating DSG2 gene mutations in a significant number of ARVC-unrelated probands. Cardiac phenotype is characterized clinically by typical ARVC features with frequent left ventricular involvement and morphologically by fibrofatty myocardial replacement and desmosomal remodeling. The presence of mutations in desmosomal encoding genes in 40% of cases confirms that many forms of ARVC are due to alterations in the desmosome complex.

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