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

Rajkumar, Revathi and Sembrat, John C and McDonough, Barbara and Seidman, Christine E and Ahmad, Ferhaan (2012) Functional effects of the TMEM43 Ser358Leu mutation in the pathogenesis of arrhythmogenic right ventricular cardiomyopathy. BMC Medical Genetics, 13 (1).

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Abstract

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

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Details

Item Type:	Article
Status:	Published
Creators/Authors:	Creators Email Pitt Username ORCID Rajkumar, Revathi Sembrat, John C jcs75@pitt.edu JCS75 McDonough, Barbara Seidman, Christine E Ahmad, Ferhaan
Date:	December 2012
Date Type:	Publication
Journal or Publication Title:	BMC Medical Genetics
Volume:	13
Number:	1
Publisher:	Springer Science and Business Media LLC
DOI or Unique Handle:	10.1186/1471-2350-13-21
Schools and Programs:	School of Public Health > Human Genetics School of Medicine > Medicine
Refereed:	Yes
Date Deposited:	01 Nov 2016 18:34
Last Modified:	05 Sep 2021 14:55
URI:	http://d-scholarship.pitt.edu/id/eprint/29936

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