title: Mutation analysis and evaluation of the cardiac localization of TMEM43 in arrhythmogenic right ventricular cardiomyopathy.
abstract: 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.
authors.affiliation: Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Denmark. alexhc@dadlnet.dk
authors.forename: A H
authors.initials: AH
authors.lastname: Christensen
authors.forename: C B
authors.initials: CB
authors.lastname: Andersen
authors.forename: A
authors.initials: A
authors.lastname: Tybjaerg-Hansen
authors.forename: S
authors.initials: S
authors.lastname: Haunso
authors.forename: J H
authors.initials: JH
authors.lastname: Svendsen
mesh_terms: D000293:Adolescent; D000328:Adult; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D018031:Connexin 43 / Q000235:genetics; D004252:DNA Mutational Analysis; D003718:Denmark; D051180:Desmoplakins / Q000235:genetics* / Q000378:metabolism; D003896:Desmosomes / Q000235:genetics*; D005260:Female; D005820:Genetic Testing; D006579:Heterozygote; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics; D010375:Pedigree; D051191:Plakophilins / Q000235:genetics; D051185:gamma Catenin
chemical_list: D018031:Connexin 43; D051180:Desmoplakins; C495292:JUP protein, human; D008565:Membrane Proteins; D009687:Nuclear Proteins; D051191:Plakophilins; C528696:TMEM43 protein, human; C092710:emerin; D051185:gamma Catenin