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

Circulation. 2014 Mar 11;129(10):1092-103. doi: 10.1161/CIRCULATIONAHA.113.003077. Epub 2013 Dec 18.


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.

Keywords: Brugada syndrome; arrhythmogenic right ventricular dysplasia-cardiomyopathy; desmosomes; plakophilin 2; sodium channels.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Brugada Syndrome / genetics*
  • Brugada Syndrome / metabolism*
  • Brugada Syndrome / physiopathology
  • Cell Line
  • Disease Models, Animal
  • Female
  • Genotype
  • Heart Conduction System / physiopathology
  • Humans
  • Male
  • Mice
  • Mice, Mutant Strains
  • Middle Aged
  • Mutation, Missense
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • NAV1.5 Voltage-Gated Sodium Channel / metabolism
  • Patch-Clamp Techniques
  • Pedigree
  • Phenotype*
  • Plakophilins / genetics*
  • Retrospective Studies
  • Sodium Channels / deficiency*
  • Sodium Channels / metabolism


  • NAV1.5 Voltage-Gated Sodium Channel
  • PKP2 protein, human
  • Pkp2 protein, mouse
  • Plakophilins
  • Scn5a protein, mouse
  • Sodium Channels