Arrhythmogenic right ventricular cardiomyopathy type 5 is a fully penetrant, lethal arrhythmic disorder caused by a missense mutation in the TMEM43 gene

Item Type:	Article
Title:	Arrhythmogenic right ventricular cardiomyopathy type 5 is a fully penetrant, lethal arrhythmic disorder caused by a missense mutation in the TMEM43 gene
Creators Name:	Merner, N.D. and Hodgkinson, K.A. and Haywood, A.F. and Connors, S. and French, V.M. and Drenckhahn, J.D. and Kupprion, C. and Ramadanova, K. and Thierfelder, L. and McKenna, W. and Gallagher, B. and Morris-Larkin, L. and Bassett, A.S. and Parfrey, P.S. and Young, T.L.
Abstract:	Autosomal-dominant arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) causes sudden cardiac death and is characterized by clinical and genetic heterogeneity. Fifteen unrelated ARVC families with a disease-associated haplotype on chromosome 3p (ARVD5) were ascertained from a genetically isolated population. Identification of key recombination events reduced the disease region to a 2.36 Mb interval containing 20 annotated genes. Bidirectional resequencing showed one rare variant in transmembrane protein 43 (TMEM43 1073C-->T, S358L), was carried on all recombinant ARVD5 ancestral haplotypes from affected subjects and not found in population controls. The mutation occurs in a highly conserved transmembrane domain of TMEM43 and is predicted to be deleterious. Clinical outcomes in 257 affected and 151 unaffected subjects were compared, and penetrance was determined. We concluded that ARVC at locus ARVD5 is a lethal, fully penetrant, sex-influenced morbid disorder. Median life expectancy was 41 years in affected males compared to 71 years in affected females (relative risk 6.8, 95% CI 1.3-10.9). Heart failure was a late manifestation in survivors. Although little is known about the function of the TMEM43 gene, it contains a response element for PPARgamma (an adipogenic transcription factor), which may explain the fibrofatty replacement of the myocardium, a characteristic pathological finding in ARVC.
Keywords:	Amino Acid Sequence, Arrhythmogenic Right Ventricular Dysplasia, Human Pair 3 Chromosomes, DNA Mutational Analysis, Genetic Screening, Heart Failure, Life Expectancy, Membrane Proteins, Molecular Sequence Data, Missense Mutation, Myocardium, Pedigree, Penetrance, Physical Chromosome Mapping, Protein Conformation, Sex Factors
Source:	American Journal of Human Genetics
ISSN:	0002-9297
Publisher:	Cell Press
Volume:	82
Number:	4
Page Range:	809-821
Date:	11 April 2008
Official Publication:	https://doi.org/10.1016/j.ajhg.2008.01.010
PubMed:	View item in PubMed

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