Missense Mutations in Plakophilin-2 Cause Sodium Current Deficit and Associate With a Brugada Syndrome Phenotype

Article

关键词: RIGHT-VENTRICULAR CARDIOMYOPATHY;    INTERCALATED DISC;    GAP-JUNCTIONS;    SUDDEN-DEATH;    CONNEXIN43;    CHANNEL;    ABNORMALITIES;    PROTEINS;    DYSPLASIA/CARDIOMYOPATHY;    PLAKOGLOBIN;   

DOI  :  10.1161/CIRCULATIONAHA.113.003077

来源: SCIE

【 摘 要 】

Background-Brugada syndrome (BrS) primarily associates with the loss of sodium channel function. Previous studies showed features consistent with sodium current (I-Na) 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 I-Na. We hypothesized that PKP2 variants that reduce I-Na 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 Na(V)1.5 but made deficient in PKP2 (PKP2-KD). Loss of PKP2 caused decreased I-Na and Na(V)1.5 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 I-Na. The deficit was restored by transfection of wild type, but not BrS-related PKP2. Super-resolution microscopy in murine PKP2-deficient cardiomyocytes related I-Na 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.

【 授权许可】

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