Functional effects of the TMEM43 Ser358Leu mutation in the pathogenesis of arrhythmogenic right ventricular cardiomyopathy

To determine the frequency of TMEM43 mutations as a cause of ARVC, we screened 11 ARVC families for mutations in TMEM43 and five desmosomal genes previously implicated in the disease. Functional studies were performed in COS-7 cells transfected with wildtype, mutant, and 1:2 wildtype:mutant TMEM43 to determine the effect of the Ser358Leu mutation on the stability and cellular localization of TMEM43 and other nuclear envelope and desmosomal proteins, assessed by solubility assays and immunofluorescence imaging. mRNA expression was assessed of genes potentially affected by dysfunction of the nuclear lamina.Three novel mutations in previously documented desmosomal genes, but no mutations in TMEM43, were identified. COS-7 cells transfected with mutant TMEM43 exhibited no change in desmosomal stability. Stability and nuclear membrane localization of mutant TMEM43 and of lamin B and emerin were normal. Mutant TMEM43 did not alter the expression of genes located on chromosome 13, previously implicated in nuclear envelope protein mutations leading to skeletal muscular dystrophies.Mutant TMEM43 exhibits normal cellular localization and does not disrupt integrity and localization of other nuclear envelope and desmosomal proteins. The pathogenetic role of TMEM43 mutations in ARVC remains uncertain.Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) is an inherited disorder characterized by replacement of cardiomyocytes by adipose and fibrous tissue, primarily in the right ventricle (RV). This disruption can result in RV dysfunction, arrhythmias and sudden cardiac death. In the United States, 17% of sudden death victims between the ages of 20 and 40 years had ARVC. A large number of cases are unrecognized because clinical tests are relatively insensitive to in vivo detection of functional and structural changes in the RV [1,2]. In approximately 40% of patients, mutations have been identified in genes encoding constituent proteins of cardiac desmosomes, namely, desm