| Summary: | <p>Abstract</p> <p>Background</p> <p>The Ser358Leu mutation in <it>TMEM43</it>, encoding an inner nuclear membrane protein, has been implicated in arrhythmogenic right ventricular cardiomyopathy (ARVC). The pathogenetic mechanisms of this mutation are poorly understood.</p> <p>Methods</p> <p>To determine the frequency of <it>TMEM43 </it>mutations as a cause of ARVC, we screened 11 ARVC families for mutations in <it>TMEM43 </it>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 <it>TMEM43 </it>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.</p> <p>Results</p> <p>Three novel mutations in previously documented desmosomal genes, but no mutations in <it>TMEM43</it>, were identified. COS-7 cells transfected with mutant <it>TMEM43 </it>exhibited no change in desmosomal stability. Stability and nuclear membrane localization of mutant TMEM43 and of lamin B and emerin were normal. Mutant <it>TMEM43 </it>did not alter the expression of genes located on chromosome 13, previously implicated in nuclear envelope protein mutations leading to skeletal muscular dystrophies.</p> <p>Conclusions</p> <p>Mutant <it>TMEM43 </it>exhibits normal cellular localization and does not disrupt integrity and localization of other nuclear envelope and desmosomal proteins. The pathogenetic role of <it>TMEM43 </it>mutations in ARVC remains uncertain.</p>
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