The TMEM43 Newfoundland mutation p.S358L causing ARVC-5 was imported from Europe and increases the stiffness of the cell nucleus

Milting H, Klauke B, Christensen AH, Müsebeck J, Walhorn V, Grannemann S, Münnich T, Šarić T, Rasmussen TB, Jensen HK, Mogensen J, et al. (2015)
European Heart Journal 36(14): 872-881.

Zeitschriftenaufsatz | Veröffentlicht | Englisch
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Milting, Hendrik; Klauke, Bärbel; Christensen, Alex Hoerby; Müsebeck, Jörg; Walhorn, VolkerUniBi; Grannemann, SörenUniBi; Münnich, TamaraUniBi; Šarić, Tomo; Rasmussen, Torsten Bloch; Jensen, Henrik Kjærulf; Mogensen, Jens; Baecker, Carolin
Abstract / Bemerkung
AIMS: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare genetic condition caused predominantly by mutations within desmosomal genes. The mutation leading to ARVC-5 was recently identified on the island of Newfoundland and caused by the fully penetrant missense mutation p.S358L in TMEM43. Although TMEM43-p.S358L mutation carriers were also found in the USA, Germany, and Denmark, the genetic relationship between North American and European patients and the disease mechanism of this mutation remained to be clarified. METHODS AND RESULTS: We screened 22 unrelated ARVC patients without mutations in desmosomal genes and identified the TMEM43-p.S358L mutation in a German ARVC family. We excluded TMEM43-p.S358L in 22 unrelated patients with dilated cardiomyopathy. The German family shares a common haplotype with those from Newfoundland, USA, and Denmark, suggesting that the mutation originated from a common founder. Examination of 40 control chromosomes revealed an estimated age of 1300-1500 years for the mutation, which proves the European origin of the Newfoundland mutation. Skin fibroblasts from a female and two male mutation carriers were analysed in cell culture using atomic force microscopy and revealed that the cell nuclei exhibit an increased stiffness compared with TMEM43 wild-type controls. CONCLUSION: The German family is not affected by a de novo TMEM43 mutation. It is therefore expected that an unknown number of European families may be affected by the TMEM43-p.S358L founder mutation. Due to its deleterious clinical phenotype, this mutation should be checked in any case of ARVC-related genotyping. It appears that the increased stiffness of the cell nucleus might be related to the massive loss of cardiomyocytes, which is typically found in ventricles of ARVC hearts.
European Heart Journal
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Milting H, Klauke B, Christensen AH, et al. The TMEM43 Newfoundland mutation p.S358L causing ARVC-5 was imported from Europe and increases the stiffness of the cell nucleus. European Heart Journal. 2015;36(14):872-881.
Milting, H., Klauke, B., Christensen, A. H., Müsebeck, J., Walhorn, V., Grannemann, S., Münnich, T., et al. (2015). The TMEM43 Newfoundland mutation p.S358L causing ARVC-5 was imported from Europe and increases the stiffness of the cell nucleus. European Heart Journal, 36(14), 872-881. doi:10.1093/eurheartj/ehu077
Milting, H., Klauke, B., Christensen, A. H., Müsebeck, J., Walhorn, V., Grannemann, S., Münnich, T., Šarić, T., Rasmussen, T. B., Jensen, H. K., et al. (2015). The TMEM43 Newfoundland mutation p.S358L causing ARVC-5 was imported from Europe and increases the stiffness of the cell nucleus. European Heart Journal 36, 872-881.
Milting, H., et al., 2015. The TMEM43 Newfoundland mutation p.S358L causing ARVC-5 was imported from Europe and increases the stiffness of the cell nucleus. European Heart Journal, 36(14), p 872-881.
H. Milting, et al., “The TMEM43 Newfoundland mutation p.S358L causing ARVC-5 was imported from Europe and increases the stiffness of the cell nucleus”, European Heart Journal, vol. 36, 2015, pp. 872-881.
Milting, H., Klauke, B., Christensen, A.H., Müsebeck, J., Walhorn, V., Grannemann, S., Münnich, T., Šarić, T., Rasmussen, T.B., Jensen, H.K., Mogensen, J., Baecker, C., Romaker, E., Laser, K.T., zu Knyphausen, E., Kassner, A., Gummert, J., Judge, D.P., Connors, S., Hodgkinson, K., Young, T.-L., van der Zwaag, P.A., van Tintelen, J.P., Anselmetti, D.: The TMEM43 Newfoundland mutation p.S358L causing ARVC-5 was imported from Europe and increases the stiffness of the cell nucleus. European Heart Journal. 36, 872-881 (2015).
Milting, Hendrik, Klauke, Bärbel, Christensen, Alex Hoerby, Müsebeck, Jörg, Walhorn, Volker, Grannemann, Sören, Münnich, Tamara, Šarić, Tomo, Rasmussen, Torsten Bloch, Jensen, Henrik Kjærulf, Mogensen, Jens, Baecker, Carolin, Romaker, Elena, Laser, Kai Thorsten, zu Knyphausen, Edzard, Kassner, Astrid, Gummert, Jan, Judge, Daniel P., Connors, Sean, Hodgkinson, Kathy, Young, Terry-L., van der Zwaag, Paul A., van Tintelen, J. Peter, and Anselmetti, Dario. “The TMEM43 Newfoundland mutation p.S358L causing ARVC-5 was imported from Europe and increases the stiffness of the cell nucleus”. European Heart Journal 36.14 (2015): 872-881.

15 Zitationen in Europe PMC

Daten bereitgestellt von Europe PubMed Central.

TMEM43-S358L mutation enhances NF-κB-TGFβ signal cascade in arrhythmogenic right ventricular dysplasia/cardiomyopathy.
Zheng G, Jiang C, Li Y, Yang D, Ma Y, Zhang B, Li X, Zhang P, Hu X, Zhao X, Du J, Lin X., Protein Cell 10(2), 2019
PMID: 29980933
Novel Desmin Mutation p.Glu401Asp Impairs Filament Formation, Disrupts Cell Membrane Integrity, and Causes Severe Arrhythmogenic Left Ventricular Cardiomyopathy/Dysplasia.
Bermúdez-Jiménez FJ, Carriel V, Brodehl A, Alaminos M, Campos A, Schirmer I, Milting H, Abril BÁ, Álvarez M, López-Fernández S, García-Giustiniani D, Monserrat L, Tercedor L, Jiménez-Jáimez J., Circulation 137(15), 2018
PMID: 29212896
Luma is not essential for murine cardiac development and function.
Stroud MJ, Fang X, Zhang J, Guimarães-Camboa N, Veevers J, Dalton ND, Gu Y, Bradford WH, Peterson KL, Evans SM, Gerace L, Chen J., Cardiovasc Res 114(3), 2018
PMID: 29040414
LUMA in cardiac development and function.
Liu Y, Chen VHS, Shou W., Cardiovasc Res 114(3), 2018
PMID: 29281017
A novel desmin mutation causing severe left ventricular arrhythmogenic cardiomyopathy/dysplasia.
Bazoukis G, Letsas KP, Xia Y, Tse G, Li KHC., J Thorac Dis 10(suppl 26), 2018
PMID: 30370089
A common variant in CLDN14 causes precipitous, prelingual sensorineural hearing loss in multiple families due to founder effect.
Pater JA, Benteau T, Griffin A, Penney C, Stanton SG, Predham S, Kielley B, Squires J, Zhou J, Li Q, Abdelfatah N, O'Rielly DD, Young TL., Hum Genet 136(1), 2017
PMID: 27838790
Arrhythmogenic Right Ventricular Cardiomyopathy.
Corrado D, Link MS, Calkins H., N Engl J Med 376(15), 2017
PMID: 28402769
Redefining the role of biomarkers in heart failure trials: expert consensus document.
Kramer F, Sabbah HN, Januzzi JJ, Zannad F, Peter van Tintelen J, Schelbert EB, Kim RJ, Milting H, Vonk R, Neudeck B, Clark R, Witte K, Dinh W, Pieske B, Butler J, Gheorghiade M., Heart Fail Rev 22(3), 2017
PMID: 28332132
Arrhythmogenic cardiomyopathy: pathology, genetics, and concepts in pathogenesis.
Hoorntje ET, Te Rijdt WP, James CA, Pilichou K, Basso C, Judge DP, Bezzina CR, van Tintelen JP., Cardiovasc Res 113(12), 2017
PMID: 28957532
Long-Term Clinical Outcome of Arrhythmogenic Right Ventricular Cardiomyopathy in Individuals With a p.S358L Mutation in TMEM43 Following Implantable Cardioverter Defibrillator Therapy.
Hodgkinson KA, Howes AJ, Boland P, Shen XS, Stuckless S, Young TL, Curtis F, Collier A, Parfrey PS, Connors SP., Circ Arrhythm Electrophysiol 9(3), 2016
PMID: 26966288
Failure of ICD therapy in lethal arrhythmogenic right ventricular cardiomyopathy type 5 caused by the TMEM43 p.Ser358Leu mutation.
Aalbæk Kjærgaard K, Kristensen J, Mølgaard H, Cosedis Nielsen J, Jensen HK., HeartRhythm Case Rep 2(3), 2016
PMID: 28491673
Arrhythmogenic Cardiomyopathy: Electrical and Structural Phenotypes.
Akdis D, Brunckhorst C, Duru F, Saguner AM., Arrhythm Electrophysiol Rev 5(2), 2016
PMID: 27617087
Arrhythmias, syncopy, and sudden death.
Lüscher TF., Eur Heart J 36(14), 2015
PMID: 25850666

40 References

Daten bereitgestellt von Europe PubMed Central.

De novo desmin-mutation N116S is associated with arrhythmogenic right ventricular cardiomyopathy.
Klauke B, Kossmann S, Gaertner A, Brand K, Stork I, Brodehl A, Dieding M, Walhorn V, Anselmetti D, Gerdes D, Bohms B, Schulz U, Zu Knyphausen E, Vorgerd M, Gummert J, Milting H., Hum. Mol. Genet. 19(23), 2010
PMID: 20829228
Desmosomal gene analysis in arrhythmogenic right ventricular dysplasia/cardiomyopathy: spectrum of mutations and clinical impact in practice.
Fressart V, Duthoit G, Donal E, Probst V, Deharo JC, Chevalier P, Klug D, Dubourg O, Delacretaz E, Cosnay P, Scanu P, Extramiana F, Keller D, Hidden-Lucet F, Simon F, Bessirard V, Roux-Buisson N, Hebert JL, Azarine A, Casset-Senon D, Rouzet F, Lecarpentier Y, Fontaine G, Coirault C, Frank R, Hainque B, Charron P., Europace 12(6), 2010
PMID: 20400443
Arrhythmogenic right ventricular cardiomyopathy type 5 is a fully penetrant, lethal arrhythmic disorder caused by a missense mutation in the TMEM43 gene.
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., Am. J. Hum. Genet. 82(4), 2008
PMID: 18313022
The natural history of a genetic subtype of arrhythmogenic right ventricular cardiomyopathy caused by a p.S358L mutation in TMEM43.
Hodgkinson KA, Connors SP, Merner N, Haywood A, Young TL, McKenna WJ, Gallagher B, Curtis F, Bassett AS, Parfrey PS., Clin. Genet. 83(4), 2012
PMID: 22725725
Mutation analysis and evaluation of the cardiac localization of TMEM43 in arrhythmogenic right ventricular cardiomyopathy.
Christensen AH, Andersen CB, Tybjaerg-Hansen A, Haunso S, Svendsen JH., Clin. Genet. 80(3), 2011
PMID: 21214875

AUTHOR UNKNOWN, Cell Tissue Res. 348(), 2012
TMEM43 mutations associated with arrhythmogenic right ventricular cardiomyopathy in non-Newfoundland populations.
Baskin B, Skinner JR, Sanatani S, Terespolsky D, Krahn AD, Ray PN, Scherer SW, Hamilton RM., Hum. Genet. 132(11), 2013
PMID: 23812740
Mutations in the Lamin A/C gene mimic arrhythmogenic right ventricular cardiomyopathy.
Quarta G, Syrris P, Ashworth M, Jenkins S, Zuborne Alapi K, Morgan J, Muir A, Pantazis A, McKenna WJ, Elliott PM., Eur. Heart J. 33(9), 2011
PMID: 22199124
TMEM43 mutations in Emery-Dreifuss muscular dystrophy-related myopathy.
Liang WC, Mitsuhashi H, Keduka E, Nonaka I, Noguchi S, Nishino I, Hayashi YK., Ann. Neurol. 69(6), 2011
PMID: 21391237
Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the Task Force Criteria.
Marcus FI, McKenna WJ, Sherrill D, Basso C, Bauce B, Bluemke DA, Calkins H, Corrado D, Cox MG, Daubert JP, Fontaine G, Gear K, Hauer R, Nava A, Picard MH, Protonotarios N, Saffitz JE, Sanborn DM, Steinberg JS, Tandri H, Thiene G, Towbin JA, Tsatsopoulou A, Wichter T, Zareba W., Eur. Heart J. 31(7), 2010
PMID: 20172912
Prevalence of desmosomal protein gene mutations in patients with dilated cardiomyopathy.
Elliott P, O'Mahony C, Syrris P, Evans A, Rivera Sorensen C, Sheppard MN, Carr-White G, Pantazis A, McKenna WJ., Circ Cardiovasc Genet 3(4), 2010
PMID: 20716751
Composite polymorphisms in the ryanodine receptor 2 gene associated with arrhythmogenic right ventricular cardiomyopathy.
Milting H, Lukas N, Klauke B, Korfer R, Perrot A, Osterziel KJ, Vogt J, Peters S, Thieleczek R, Varsanyi M., Cardiovasc. Res. 71(3), 2006
PMID: 16769042
Screening for a BRCA2 rearrangement in high-risk breast/ovarian cancer families: evidence for a founder effect and analysis of the associated phenotypes.
Machado PM, Brandao RD, Cavaco BM, Eugenio J, Bento S, Nave M, Rodrigues P, Fernandes A, Vaz F., J. Clin. Oncol. 25(15), 2007
PMID: 17513806
Unraveling heterochromatin.
Briggs SD, Strahl BD., Nat. Genet. 30(3), 2002
PMID: 11919553
In vitro modeling of ryanodine receptor 2 dysfunction using human induced pluripotent stem cells.
Fatima A, Xu G, Shao K, Papadopoulos S, Lehmann M, Arnaiz-Cot JJ, Rosa AO, Nguemo F, Matzkies M, Dittmann S, Stone SL, Linke M, Zechner U, Beyer V, Hennies HC, Rosenkranz S, Klauke B, Parwani AS, Haverkamp W, Pfitzer G, Farr M, Cleemann L, Morad M, Milting H, Hescheler J, Saric T., Cell. Physiol. Biochem. 28(4), 2011
PMID: 22178870
Genetic counselling and testing in cardiomyopathies: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases.
Charron P, Arad M, Arbustini E, Basso C, Bilinska Z, Elliott P, Helio T, Keren A, McKenna WJ, Monserrat L, Pankuweit S, Perrot A, Rapezzi C, Ristic A, Seggewiss H, van Langen I, Tavazzi L; European Society of Cardiology Working Group on Myocardial and Pericardial Diseases., Eur. Heart J. 31(22), 2010
PMID: 20823110
Phospholamban R14del mutation in patients diagnosed with dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy: evidence supporting the concept of arrhythmogenic cardiomyopathy.
van der Zwaag PA, van Rijsingen IA, Asimaki A, Jongbloed JD, van Veldhuisen DJ, Wiesfeld AC, Cox MG, van Lochem LT, de Boer RA, Hofstra RM, Christiaans I, van Spaendonck-Zwarts KY, Lekanne dit Deprez RH, Judge DP, Calkins H, Suurmeijer AJ, Hauer RN, Saffitz JE, Wilde AA, van den Berg MP, van Tintelen JP., Eur. J. Heart Fail. 14(11), 2012
PMID: 22820313
Screening of three novel candidate genes in arrhythmogenic right ventricular cardiomyopathy.
Christensen AH, Benn M, Tybjærg-Hansen A, Haunso S, Svendsen JH., Genet Test Mol Biomarkers 15(4), 2011
PMID: 21254927
Arrhythmogenic cardiomyopathy: etiology, diagnosis, and treatment.
Sen-Chowdhry S, Morgan RD, Chambers JC, McKenna WJ., Annu. Rev. Med. 61(), 2010
PMID: 20059337
Nuclear envelope proteomics: novel integral membrane proteins of the inner nuclear membrane.
Dreger M, Bengtsson L, Schoneberg T, Otto H, Hucho F., Proc. Natl. Acad. Sci. U.S.A. 98(21), 2001
PMID: 11593002
Pathophysiology of arrhythmogenic cardiomyopathy.
Basso C, Bauce B, Corrado D, Thiene G., Nat Rev Cardiol 9(4), 2011
PMID: 22124316
Molecular insights into arrhythmogenic right ventricular cardiomyopathy caused by plakophilin-2 missense mutations.
Kirchner F, Schuetz A, Boldt LH, Martens K, Dittmar G, Haverkamp W, Thierfelder L, Heinemann U, Gerull B., Circ Cardiovasc Genet 5(4), 2012
PMID: 22781308
In vitro functional analyses of arrhythmogenic right ventricular cardiomyopathy-associated desmoglein-2-missense variations.
Gaertner A, Klauke B, Stork I, Niehaus K, Niemann G, Gummert J, Milting H., PLoS ONE 7(10), 2012
PMID: 23071725
Havekes B, Pacak K., Nat Clin Pract Cardiovasc Med 5(2), 2008
PMID: 18223538
Molecular genetics of arrhythmogenic right ventricular dysplasia/cardiomyopathy.
Milting H, Klauke B., Nat Clin Pract Cardiovasc Med 5(10), 2008
PMID: 18813333
A missense variant in desmoglein-2 predisposes to dilated cardiomyopathy.
Posch MG, Posch MJ, Geier C, Erdmann B, Mueller W, Richter A, Ruppert V, Pankuweit S, Maisch B, Perrot A, Buttgereit J, Dietz R, Haverkamp W, Ozcelik C., Mol. Genet. Metab. 95(1-2), 2008
PMID: 18678517
Localization of a gene responsible for arrhythmogenic right ventricular dysplasia to chromosome 3p23.
Ahmad F, Li D, Karibe A, Gonzalez O, Tapscott T, Hill R, Weilbaecher D, Blackie P, Furey M, Gardner M, Bachinski LL, Roberts R., Circulation 98(25), 1998
PMID: 9860777
The Newfoundland population: a unique resource for genetic investigation of complex diseases.
Rahman P, Jones A, Curtis J, Bartlett S, Peddle L, Fernandez BA, Freimer NB., Hum. Mol. Genet. 12 Spec No 2(), 2003
PMID: 12915452
Recurrent missense mutations in TMEM43 (ARVD5) due to founder effects cause arrhythmogenic cardiomyopathies in the UK and Canada.
Haywood AF, Merner ND, Hodgkinson KA, Houston J, Syrris P, Booth V, Connors S, Pantazis A, Quarta G, Elliott P, McKenna W, Young TL., Eur. Heart J. 34(13), 2012
PMID: 23161701
LINC complexes in health and disease.
Mejat A, Misteli T., Nucleus 1(1), 2010
PMID: 21327104
Functional effects of the TMEM43 Ser358Leu mutation in the pathogenesis of arrhythmogenic right ventricular cardiomyopathy.
Rajkumar R, Sembrat JC, McDonough B, Seidman CE, Ahmad F., BMC Med. Genet. 13(), 2012
PMID: 22458570
Diseases of the nuclear envelope.
Worman HJ, Ostlund C, Wang Y., Cold Spring Harb Perspect Biol 2(2), 2010
PMID: 20182615
Lamin A/C deficiency causes defective nuclear mechanics and mechanotransduction.
Lammerding J, Schulze PC, Takahashi T, Kozlov S, Sullivan T, Kamm RD, Stewart CL, Lee RT., J. Clin. Invest. 113(3), 2004
PMID: 14755334
Myopathic lamin mutations impair nuclear stability in cells and tissue and disrupt nucleo-cytoskeletal coupling.
Zwerger M, Jaalouk DE, Lombardi ML, Isermann P, Mauermann M, Dialynas G, Herrmann H, Wallrath LL, Lammerding J., Hum. Mol. Genet. 22(12), 2013
PMID: 23427149
Nuclear accumulation of androgen receptor in gender difference of dilated cardiomyopathy due to lamin A/C mutations.
Arimura T, Onoue K, Takahashi-Tanaka Y, Ishikawa T, Kuwahara M, Setou M, Shigenobu S, Yamaguchi K, Bertrand AT, Machida N, Takayama K, Fukusato M, Tanaka R, Somekawa S, Nakano T, Yamane Y, Kuba K, Imai Y, Saito Y, Bonne G, Kimura A., Cardiovasc. Res. 99(3), 2013
PMID: 23631840
Exercise increases age-related penetrance and arrhythmic risk in arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated desmosomal mutation carriers.
James CA, Bhonsale A, Tichnell C, Murray B, Russell SD, Tandri H, Tedford RJ, Judge DP, Calkins H., J. Am. Coll. Cardiol. 62(14), 2013
PMID: 23871885


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