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

Revathi Rajkumar1, John C Sembrat1, Barbara McDonough2, Christine E Seidman2 and Ferhaan Ahmad134*

Author Affiliations

1 UPMC Heart and Vascular Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA

2 Department of Genetics, Harvard Medical School and Howard Hughes Medical Institute, Boston, MA 02115, USA

3 Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA 15213, USA

4 UPMC Heart and Vascular Institute, University of Pittsburgh, 200 Lothrop Street, Scaife Hall Suite S-558, Mail Stop HPU 01 05 05, Pittsburgh, PA 15213-2582, USA

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BMC Medical Genetics 2012, 13:21  doi:10.1186/1471-2350-13-21

Published: 29 March 2012



The Ser358Leu mutation in TMEM43, encoding an inner nuclear membrane protein, has been implicated in arrhythmogenic right ventricular cardiomyopathy (ARVC). The pathogenetic mechanisms of this mutation are poorly understood.


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.