title: Functional effects of the TMEM43 Ser358Leu mutation in the pathogenesis of arrhythmogenic right ventricular cardiomyopathy.
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.
authors.affiliation: UPMC Heart and Vascular Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Revathi
authors.initials: R
authors.lastname: Rajkumar
authors.forename: John C
authors.initials: JC
authors.lastname: Sembrat
authors.forename: Barbara
authors.initials: B
authors.lastname: McDonough
authors.forename: Christine E
authors.initials: CE
authors.lastname: Seidman
authors.forename: Ferhaan
authors.initials: F
authors.lastname: Ahmad
mesh_terms: D000818:Animals; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000235:genetics* / Q000503:physiopathology; D019556:COS Cells; D002522:Chlorocebus aethiops; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D008856:Microscopy, Fluorescence; D020125:Mutation, Missense / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D014162:Transfection
chemical_list: D008565:Membrane Proteins; C528696:TMEM43 protein, human