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Mutation analysis and evaluation of the cardiac localization of TMEM43 in arrhythmogenic right ventricular cardiomyopathy

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A single report has associated mutations in TMEM43 (LUMA) with a distinctive form of arrhythmogenic right ventricular cardiomyopathy (ARVC). We aimed at performing mutational analysis of the gene and characterizing the associated immunohistochemical features. Sixty-five unrelated patients (55 fulfilling Task Force criteria and 10 borderline cases) were screened for mutations in TMEM43. Immunohistochemistry with anti-TMEM43, anti-plakoglobin, anti-plakophilin-2, anti-connexin-43, and anti-emerin antibodies was performed on myocardium from TMEM43-positive patients (n = 3) and healthy controls (n = 3). The genetic screening identified heterozygous variants in two families: one reported mutation (c.1073C> T; in two related patients) and one novel variant (c.705+ 7G> A; in one patient) of unknown significance. All three patients fulfilled Task Force criteria and did not carry mutations in any other ARVC-related gene. Immunostaining with TMEM43 antibody showed intense staining of the sarcolemma. The signal level was reduced in all the three TMEM43-positive patients. Immunostaining with plakoglobin-specific antibody also showed reduced signal levels in the three carriers. All patients displayed a similar immunoreactive signal for plakophilin-2, connexin-43, and emerin. In conclusion, two TMEM43 sequence variants were identified in this Danish ARVC cohort. Evaluation of the expression of TMEM43 showed a unique cardiac localization. The immunoreactive signal for the desmosomal protein plakoglobin was reduced in mutation carriers. The TMEM43 gene underlies a distinctive form of ARVC which may share a final common pathway with desmosome-associated ARVC.
Original languageEnglish
JournalClinical Genetics
Volume80
Issue number3
Pages (from-to)256-64
Number of pages9
ISSN0009-9163
DOIs
Publication statusPublished - 2011

    Research areas

  • Adolescent, Adult, Arrhythmogenic Right Ventricular Dysplasia, Case-Control Studies, Child, Child, Preschool, Cohort Studies, Connexin 43, DNA Mutational Analysis, Denmark, Desmoplakins, Desmosomes, Female, Genetic Testing, Heterozygote, Humans, Immunohistochemistry, Male, Membrane Proteins, Middle Aged, Mutation, Myocardium, Nuclear Proteins, Pedigree, Plakophilins

ID: 33197393