Recurrent missense mutations in TMEM43 (ARVD5) due to founder effects cause arrhythmogenic cardiomyopathies in the UK and Canada
Type
ArticleAuthors
Haywood, AnnikaMerner, Nancy D.
Hodgkinson, Kathy A.
Houston, Jim
Syrris, Petros
Booth, Valerie
Connors, Sean
Pantazis, Antonios
Quarta, Giovanni
Elliott, Perry
McKenna, William
Young, Terry Lynn
KAUST Department
Biological and Environmental Sciences and Engineering (BESE) DivisionComputational Bioscience Research Center (CBRC)
Date
2012-11-15Online Publication Date
2012-11-15Print Publication Date
2013-04-01Permanent link to this record
http://hdl.handle.net/10754/594089
Metadata
Show full item recordAbstract
AimsAutosomal 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.Citation
Haywood 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.Sponsors
This 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.Publisher
Oxford University Press (OUP)Journal
European Heart JournalPubMed ID
23161701ae974a485f413a2113503eed53cd6c53
10.1093/eurheartj/ehs383
Scopus Count
Related articles
- 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
- Clinical characteristics and determinants of the phenotype in TMEM43 arrhythmogenic right ventricular cardiomyopathy type 5.
- Authors: Dominguez F, Zorio E, Jimenez-Jaimez J, Salguero-Bodes R, Zwart R, Gonzalez-Lopez E, Molina P, Bermúdez-Jiménez F, Delgado JF, Braza-Boïls A, Bornstein B, Toquero J, Segovia J, Van Tintelen JP, Lara-Pezzi E, Garcia-Pavia P
- Issue date: 2020 Jun
- 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
- 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