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• W2045782405 abstract "Background Brugada syndrome (BrS) is associated with 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 ([AC]; or arrhythmogenic right ventricular cardiomyopathy [ARVC]). Experimental models showed correlation between 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 cardiomyopathic features of AC. Methods and Results We searched for PKP2 variants in genomic DNA of 200 patients with BrS diagnosis, no signs of AC, and no mutations in BrS-related genes SCN5A, CACNa1c, GPD1L, and MOG1 . We identified 5 cases of single amino acid substitutions. One (Q62K) was previously described in AC patients as a variant of unknown significance; 4 were unreported. In a family with multiple cases of syncope and/or suspect ECG, novel variant R635Q cosegregated with the phenotype in all affected relatives and was absent in the nonaffected ones. 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 site of cell contact. These deficits were restored by transfection of wild-type PKP2 (PKP2-WT) but not of BrS-related PKP2 mutants. Similar results were obtained when cells were cotransfected with PKP2-WT and the BrS-related PKP2 variants, to mimic heterozygosity. Human-induced pluripotent stem cell cardiomyocytes (hiPSC-CMs) from a patient with PKP2 deficit showed drastically reduced I Na . The deficit was restored by transfection of WT but not BrS-related PKP2 variant R635Q. Superresolution microscopy in murine PKP2-deficient cardiomyocytes related I Na deficiency to reduced number of channels at the intercalated disk 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." @default.
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• W2045782405 date "2013-11-01" @default.
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• W2045782405 title "Missense Mutations in Plakophilin-2 Can Cause Brugada Syndrome Phenotype By Decreasing Sodium Current and Nav1.5 Membrane Localization" @default.
• W2045782405 doi "https://doi.org/10.1016/j.hrthm.2013.09.019" @default.
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