Abstract | BACKGROUND: 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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Authors | 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 |
Journal | Circulation
(Circulation)
Vol. 129
Issue 10
Pg. 1092-103
(Mar 11 2014)
ISSN: 1524-4539 [Electronic] United States |
PMID | 24352520
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- NAV1.5 Voltage-Gated Sodium Channel
- PKP2 protein, human
- Pkp2 protein, mouse
- Plakophilins
- Scn5a protein, mouse
- Sodium Channels
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Topics |
- Adult
- Animals
- Brugada Syndrome
(genetics, metabolism, 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, pathology)
- NAV1.5 Voltage-Gated Sodium Channel
(metabolism)
- Patch-Clamp Techniques
- Pedigree
- Phenotype
- Plakophilins
(genetics)
- Retrospective Studies
- Sodium Channels
(deficiency, metabolism)
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