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

Revathi Rajkumar; John C Sembrat; Barbara McDonough; Christine E Seidman; Ferhaan Ahmad

doi:10.1186/1471-2350-13-21

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

Journal article

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

Revathi Rajkumar, John C Sembrat, Barbara McDonough, Christine E Seidman and Ferhaan Ahmad

BMC medical genetics, Vol.13(1), pp.21-21

03/29/2012

DOI: 10.1186/1471-2350-13-21

PMCID: PMC3352248

PMID: 22458570

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Abstract

Background: 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. Methods: 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. Results: 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. Conclusions: 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.

Details

Title: Subtitle: Functional effects of the TMEM43 Ser358Leu mutation in the pathogenesis of arrhythmogenic right ventricular cardiomyopathy
Creators: Revathi Rajkumar - UPMC Heart and Vascular Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
John C Sembrat - UPMC Heart and Vascular Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
Barbara McDonough - Department of Genetics, Harvard Medical School and Howard Hughes Medical Institute, Boston, MA 02115, USA
Christine E Seidman - Department of Genetics, Harvard Medical School and Howard Hughes Medical Institute, Boston, MA 02115, USA
Ferhaan Ahmad - UPMC Heart and Vascular Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
Resource Type: Journal article
Publication Details: BMC medical genetics, Vol.13(1), pp.21-21
DOI: 10.1186/1471-2350-13-21
PMID: 22458570
PMCID: PMC3352248
NLM abbreviation: BMC Med Genet
ISSN: 1471-2350
eISSN: 1471-2350
Publisher: BioMed Central
Language: English
Date published: 03/29/2012
Academic Unit: Radiology; Molecular Physiology and Biophysics; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
Record Identifier: 9984025669202771

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