Recurrent missense mutations in TMEM43 (ARVD5) due to founder effects cause arrhythmogenic cardiomyopathies in the UK and Canada
Merner, Nancy D.
Hodgkinson, Kathy A.
Young, Terry Lynn
KAUST DepartmentBiological and Environmental Sciences and Engineering (BESE) Division
Computational Bioscience Research Center (CBRC)
MetadataShow full item record
AbstractAimsAutosomal dominant arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) (in the group of arrhythmogenic cardiomyopathies) is a common cause of sudden cardiac death in young adults. It is both clinically and genetically heterogeneous, with 12 loci (ARVC/D1-12) and eight genes identified, the majority of which encode structural proteins of cardiac desmosomes. The most recent gene identified, TMEM43, causes disease due to a missense mutation in a non-desmosomal gene (p.S358L) in 15 extended families from Newfoundland, Canada. To determine whether mutations in TMEM43 cause ARVC/D and arrhythmogenic cardiomyopathy in other populations, we fully re-sequenced TMEM43 on 143 ARVC/D probands (families) from the UK and 55 probands (from 55 families) from Newfoundland.Methods and resultsBidirectional sequencing of TMEM43 including intron-exon boundaries revealed 33 variants, the majority located in non-coding regions of TMEM43. For the purpose of validation, families of probands with rare, potentially deleterious coding variants were subjected to clinical and molecular follow-up. Three missense variants of uncertain significance (p.R28W, p.E142K, p.R312W) were located in highly conserved regions of the TMEM43 protein. One variant (p.R312W) also co-segregated with relatives showing clinical signs of disease. Genotyping and expansion of the disease-associated haplotype in subjects with the p.R312W variant from Newfoundland, Canada, and the UK suggest common ancestry.ConclusionAlthough the p.R312W variant was found in controls (3/378), identification of an ancestral disease p R312W haplotype suggests that the p.R312W variant is a pathogenic founder mutation. © 2012 The Author.
CitationHaywood AFM, Merner ND, Hodgkinson KA, Houston J, Syrris P, et al. (2012) Recurrent missense mutations in TMEM43 (ARVD5) due to founder effects cause arrhythmogenic cardiomyopathies in the UK and Canada. European Heart Journal 34: 1002–1011. Available: http://dx.doi.org/10.1093/eurheartj/ehs383.
SponsorsThis work was supported by a Genome Canada Competition III award [Atlantic Medical Genetics and Genomics Initiative (AMGGI)]; the Canadian Foundation for Innovation [New Opportunities Award (9384); Leaders Opportunity Award (13120)]; and Memorial University. Part of this work conducted in the UK was undertaken at UCLH/UCL, which received support from the Department of Health's National Institute of Health Research Biomedical Research Centres funding scheme. Dr. T.-L.Y. is supported by a Canadian Institutes of Health Research-Regional Partnerships Award salary award.
PublisherOxford University Press (OUP)
JournalEuropean Heart Journal
- The TMEM43 Newfoundland mutation p.S358L causing ARVC-5 was imported from Europe and increases the stiffness of the cell nucleus.
- Authors: Milting H, Klauke B, Christensen AH, Müsebeck J, Walhorn V, Grannemann S, Münnich T, Šarić T, Rasmussen TB, Jensen HK, Mogensen J, Baecker C, Romaker E, Laser KT, zu Knyphausen E, Kassner A, Gummert J, Judge DP, Connors S, Hodgkinson K, Young TL, van der Zwaag PA, van Tintelen JP, Anselmetti D
- Issue date: 2015 Apr 7
- TMEM43 mutations associated with arrhythmogenic right ventricular cardiomyopathy in non-Newfoundland populations.
- Authors: Baskin B, Skinner JR, Sanatani S, Terespolsky D, Krahn AD, Ray PN, Scherer SW, Hamilton RM
- Issue date: 2013 Nov
- Arrhythmogenic right ventricular cardiomyopathy type 5 is a fully penetrant, lethal arrhythmic disorder caused by a missense mutation in the TMEM43 gene.
- Authors: Merner ND, Hodgkinson KA, Haywood AF, Connors S, French VM, Drenckhahn JD, Kupprion C, Ramadanova K, Thierfelder L, McKenna W, Gallagher B, Morris-Larkin L, Bassett AS, Parfrey PS, Young TL
- Issue date: 2008 Apr
- TMEM43 mutation p.S358L alters intercalated disc protein expression and reduces conduction velocity in arrhythmogenic right ventricular cardiomyopathy.
- Authors: Siragam V, Cui X, Masse S, Ackerley C, Aafaqi S, Strandberg L, Tropak M, Fridman MD, Nanthakumar K, Liu J, Sun Y, Su B, Wang C, Liu X, Yan Y, Mendlowitz A, Hamilton RM
- Issue date: 2014
- Mutation analysis and evaluation of the cardiac localization of TMEM43 in arrhythmogenic right ventricular cardiomyopathy.
- Authors: Christensen AH, Andersen CB, Tybjaerg-Hansen A, Haunso S, Svendsen JH
- Issue date: 2011 Sep