Clin Genet 2011: 80: 256 – 264 Printed in Singapore. All rights reserved © 2011 John Wiley & Sons A/S CLINICAL GENETICS doi: 10.1111/j.1399-0004.2011.01623.x Original Article Mutation analysis and evaluation of the cardiac localization of TMEM43 in arrhythmogenic right ventricular cardiomyopathy Christensen AH, Andersen CB, Tybjærg-Hansen A, Haunso S, Svendsen JH. Mutation analysis and evaluation of the cardiac localization of TMEM43 in arrhythmogenic right ventricular cardiomyopathy. Clin Genet 2011: 80: 256–264. © John Wiley & Sons A/S, 2011 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. Conflict of interest None. AH Christensen a,b , CB Andersen c , A Tybjærg-Hansen d , S Haunso a,b,e,f and JH Svendsen a,b,f a Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, b The Danish National Research Foundation Centre for Cardiac Arrhythmia, c Department of Pathology, Rigshospitalet, Copenhagen University Hospital, d Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, e The Laboratory for Molecular Cardiology, Rigshospitalet, Copenhagen University Hospital, and f Department of Surgery and Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark Key words: ARVC – genetics – immunohistochemistry – TMEM43 Corresponding author: Alex Hørby Christensen, MD, PhD, Department of Cardiology, Section 2142, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. Tel.: +45 35 452 142; fax: +45 35 383 186; e-mail: alexhc@dadlnet.dk Received 7 July 2010, revised and accepted for publication 22 December 2010 Arrhythmogenic right ventricular cardiomyopa- thy (ARVC) is a myocardial disorder character- ized by ventricular arrhythmias, right- and/or left ventricular involvement, and fibrofatty infiltrations in the myocardium. The clinical presentation is variable, but typical symptoms include pal- pitations, dizziness, syncope, and sudden car- diac death. ARVC is diagnosed as a syndrome 256