Missense mutations in plakophilin-2 cause sodium current deficit and associate with a brugada syndrome phenotype

Marina Cerrone, Xianming Lin, Mingliang Zhang, Esperanza Agullo-Pascual, Anna Pfenniger, Halina Chkourko Gusky, Valeria Novelli, Changsung Kim, Tiara Tirasawadichai, Daniel P. Judge, Eli Rothenberg, Huei Sheng Vincent Chen, Carlo Napolitano, Silvia G. Priori, Mario Delmar

Research output: Contribution to journalArticle

Abstract

BACKGROUND - : Brugada syndrome (BrS) primarily associates with the loss of sodium channel function. Previous studies showed features consistent with sodium current (INa) deficit in patients carrying desmosomal mutations, diagnosed with arrhythmogenic cardiomyopathy (or arrhythmogenic right ventricular cardiomyopathy). Experimental models showed correlation between the loss of expression of desmosomal protein plakophilin-2 (PKP2) and reduced INa. We hypothesized that PKP2 variants that reduce INa could yield a BrS phenotype, even without overt structural features characteristic of arrhythmogenic right ventricular cardiomyopathy. METHODS AND RESULTS - : We searched for PKP2 variants in the genomic DNA of 200 patients with a BrS diagnosis, no signs of arrhythmogenic cardiomyopathy, and no mutations in BrS-related genes SCN5A, CACNa1c, GPD1L, and MOG1. We identified 5 cases of single amino acid substitutions. Mutations were tested in HL-1-derived cells endogenously expressing NaV1.5 but made deficient in PKP2 (PKP2-KD). Loss of PKP2 caused decreased INa and NaV1.5 at the site of cell contact. These deficits were restored by the transfection of wild-type PKP2, but not of BrS-related PKP2 mutants. Human induced pluripotent stem cell cardiomyocytes from a patient with a PKP2 deficit showed drastically reduced INa. The deficit was restored by transfection of wild type, but not BrS-related PKP2. Super-resolution microscopy in murine PKP2-deficient cardiomyocytes related INa deficiency to the reduced number of channels at the intercalated disc and increased separation of microtubules from the cell end. CONCLUSIONS - : This is the first systematic retrospective analysis of a patient group to define the coexistence of sodium channelopathy and genetic PKP2 variations. PKP2 mutations may be a molecular substrate leading to the diagnosis of BrS.

Original languageEnglish (US)
Pages (from-to)1092-1103
Number of pages12
JournalCirculation
Volume129
Issue number10
DOIs
StatePublished - Mar 11 2014

Fingerprint

Plakophilins
Brugada Syndrome
Missense Mutation
Sodium
Phenotype
Arrhythmogenic Right Ventricular Dysplasia
Mutation
Cardiomyopathies
Cardiac Myocytes
Transfection
Channelopathies
Induced Pluripotent Stem Cells
Cell Separation
Sodium Channels

Keywords

  • Arrhythmogenic right ventricular dysplasia-cardiomyopathy
  • Brugada syndrome
  • desmosomes
  • plakophilin 2
  • sodium channels

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Cerrone, M., Lin, X., Zhang, M., Agullo-Pascual, E., Pfenniger, A., Chkourko Gusky, H., ... Delmar, M. (2014). Missense mutations in plakophilin-2 cause sodium current deficit and associate with a brugada syndrome phenotype. Circulation, 129(10), 1092-1103. https://doi.org/10.1161/CIRCULATIONAHA.113.003077

Missense mutations in plakophilin-2 cause sodium current deficit and associate with a brugada syndrome phenotype. / Cerrone, Marina; Lin, Xianming; Zhang, Mingliang; Agullo-Pascual, Esperanza; Pfenniger, Anna; Chkourko Gusky, Halina; Novelli, Valeria; Kim, Changsung; Tirasawadichai, Tiara; Judge, Daniel P.; Rothenberg, Eli; Chen, Huei Sheng Vincent; Napolitano, Carlo; Priori, Silvia G.; Delmar, Mario.

In: Circulation, Vol. 129, No. 10, 11.03.2014, p. 1092-1103.

Research output: Contribution to journalArticle

Cerrone, M, Lin, X, Zhang, M, Agullo-Pascual, E, Pfenniger, A, Chkourko Gusky, H, Novelli, V, Kim, C, Tirasawadichai, T, Judge, DP, Rothenberg, E, Chen, HSV, Napolitano, C, Priori, SG & Delmar, M 2014, 'Missense mutations in plakophilin-2 cause sodium current deficit and associate with a brugada syndrome phenotype', Circulation, vol. 129, no. 10, pp. 1092-1103. https://doi.org/10.1161/CIRCULATIONAHA.113.003077
Cerrone M, Lin X, Zhang M, Agullo-Pascual E, Pfenniger A, Chkourko Gusky H et al. Missense mutations in plakophilin-2 cause sodium current deficit and associate with a brugada syndrome phenotype. Circulation. 2014 Mar 11;129(10):1092-1103. https://doi.org/10.1161/CIRCULATIONAHA.113.003077
Cerrone, Marina ; Lin, Xianming ; Zhang, Mingliang ; Agullo-Pascual, Esperanza ; Pfenniger, Anna ; Chkourko Gusky, Halina ; Novelli, Valeria ; Kim, Changsung ; Tirasawadichai, Tiara ; Judge, Daniel P. ; Rothenberg, Eli ; Chen, Huei Sheng Vincent ; Napolitano, Carlo ; Priori, Silvia G. ; Delmar, Mario. / Missense mutations in plakophilin-2 cause sodium current deficit and associate with a brugada syndrome phenotype. In: Circulation. 2014 ; Vol. 129, No. 10. pp. 1092-1103.
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AU - Cerrone, Marina

AU - Lin, Xianming

AU - Zhang, Mingliang

AU - Agullo-Pascual, Esperanza

AU - Pfenniger, Anna

AU - Chkourko Gusky, Halina

AU - Novelli, Valeria

AU - Kim, Changsung

AU - Tirasawadichai, Tiara

AU - Judge, Daniel P.

AU - Rothenberg, Eli

AU - Chen, Huei Sheng Vincent

AU - Napolitano, Carlo

AU - Priori, Silvia G.

AU - Delmar, Mario

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N2 - BACKGROUND - : Brugada syndrome (BrS) primarily associates with the loss of sodium channel function. Previous studies showed features consistent with sodium current (INa) deficit in patients carrying desmosomal mutations, diagnosed with arrhythmogenic cardiomyopathy (or arrhythmogenic right ventricular cardiomyopathy). Experimental models showed correlation between the loss of expression of desmosomal protein plakophilin-2 (PKP2) and reduced INa. We hypothesized that PKP2 variants that reduce INa could yield a BrS phenotype, even without overt structural features characteristic of arrhythmogenic right ventricular cardiomyopathy. METHODS AND RESULTS - : We searched for PKP2 variants in the genomic DNA of 200 patients with a BrS diagnosis, no signs of arrhythmogenic cardiomyopathy, and no mutations in BrS-related genes SCN5A, CACNa1c, GPD1L, and MOG1. We identified 5 cases of single amino acid substitutions. Mutations were tested in HL-1-derived cells endogenously expressing NaV1.5 but made deficient in PKP2 (PKP2-KD). Loss of PKP2 caused decreased INa and NaV1.5 at the site of cell contact. These deficits were restored by the transfection of wild-type PKP2, but not of BrS-related PKP2 mutants. Human induced pluripotent stem cell cardiomyocytes from a patient with a PKP2 deficit showed drastically reduced INa. The deficit was restored by transfection of wild type, but not BrS-related PKP2. Super-resolution microscopy in murine PKP2-deficient cardiomyocytes related INa deficiency to the reduced number of channels at the intercalated disc and increased separation of microtubules from the cell end. CONCLUSIONS - : This is the first systematic retrospective analysis of a patient group to define the coexistence of sodium channelopathy and genetic PKP2 variations. PKP2 mutations may be a molecular substrate leading to the diagnosis of BrS.

AB - BACKGROUND - : Brugada syndrome (BrS) primarily associates with the loss of sodium channel function. Previous studies showed features consistent with sodium current (INa) deficit in patients carrying desmosomal mutations, diagnosed with arrhythmogenic cardiomyopathy (or arrhythmogenic right ventricular cardiomyopathy). Experimental models showed correlation between the loss of expression of desmosomal protein plakophilin-2 (PKP2) and reduced INa. We hypothesized that PKP2 variants that reduce INa could yield a BrS phenotype, even without overt structural features characteristic of arrhythmogenic right ventricular cardiomyopathy. METHODS AND RESULTS - : We searched for PKP2 variants in the genomic DNA of 200 patients with a BrS diagnosis, no signs of arrhythmogenic cardiomyopathy, and no mutations in BrS-related genes SCN5A, CACNa1c, GPD1L, and MOG1. We identified 5 cases of single amino acid substitutions. Mutations were tested in HL-1-derived cells endogenously expressing NaV1.5 but made deficient in PKP2 (PKP2-KD). Loss of PKP2 caused decreased INa and NaV1.5 at the site of cell contact. These deficits were restored by the transfection of wild-type PKP2, but not of BrS-related PKP2 mutants. Human induced pluripotent stem cell cardiomyocytes from a patient with a PKP2 deficit showed drastically reduced INa. The deficit was restored by transfection of wild type, but not BrS-related PKP2. Super-resolution microscopy in murine PKP2-deficient cardiomyocytes related INa deficiency to the reduced number of channels at the intercalated disc and increased separation of microtubules from the cell end. CONCLUSIONS - : This is the first systematic retrospective analysis of a patient group to define the coexistence of sodium channelopathy and genetic PKP2 variations. PKP2 mutations may be a molecular substrate leading to the diagnosis of BrS.

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