Skip Navigation

Cardiovascular Research 2005 65(2):302-304; doi:10.1016/j.cardiores.2004.11.023
This Article
Right arrow Extract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Nattel, S.
Right arrow Articles by Schott, J.-J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Nattel, S.
Right arrow Articles by Schott, J.-J.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Copyright © 2004, European Society of Cardiology

Arrhythmogenic right ventricular dysplasia type 1 and mutations in transforming growth factor β3 gene regulatory regions: a breakthrough?

Stanley Nattela,* and Jean-Jacques Schottb

aResearch Center and Department of Medicine, Montreal Heart Institute and University of Montreal, 5000 Belanger St. E., Montreal, Quebec, Canada H1T 1C8
bINSERM U-533 and l'Institut du Thorax, University of Nantes, Nantes, France

* Corresponding author. Tel.: +1 514 376 3330; fax: +1 514 376 1355. Email address: stanley.nattel{at}icm-mhi.org

Received 16 November 2004; accepted 18 November 2004

See article by Beffagna et al. (pages 366–373) in this issue.

Arrhythmogenic right ventricular dysplasia (ARVD) is the second most common cause of sudden unexpected death in young adults [1], responsible for ~20% of sudden deaths in this population [2]. Subsequent to the description of the first case in 1961 [3], great progress has been made in the diagnosis, evaluation and management of the condition. The hallmark of ARVD is right ventricular atrophy with fibro-fatty infiltration. There is approximately threefold male predominance, and typical abnormalities include signs of right ventricular thinning and dysfunction and fragmented, low-amplitude late-QRS potentials in the right precordial leads identified on standard ("epsilon waves") or signal-averaged electrocardiograms [2]. Familial occurrence is common, and in ~30% of cases evidence has been found for autosomal-dominant inheritance with variable penetrance [4].

A variety of chromosomal locations have been identified in various kindreds with the condition (for review, see Ref. [2]). Eight subtypes identified as ARVD1–8 have been recognized. The specific gene underlying ARVD has been identified for a small number of subtypes. ARVD2, with features perhaps more typical of a catecholamine-dependent ventricular tachyarrhythmia syndrome than of ARVD, is associated with a mutation in ryanodine receptor-2 [5]. All other mutations described to date have been in genes encoding cytoskeletal proteins involved in desmosomal cell–cell interaction: plakoglobin ({gamma}-catenin), which interacts with {alpha}- and β-catenin to mediate cell–cell adhesion in cardiac and dermal–epidermal junctions and for which homozygous deficiency causes Naxos disease [6]; desmoplakin, which attaches intermediate filaments to desmosomes and which causes the autosomal-dominant ARVD8 [7,8]; and plakophilin-2, an armadillo repeat protein strongly expressed in desmosomes [9]. Presumably because of the particularly important roles of desmosomes in heart and skin, desmosomal protein mutations can produce specific cardio/cutaneous phenotypes.

The first form of ARVD connected to a chromosomal abnormality was ARVD1, linked in 1994 to a locus on 14q23–q24 [10]. Five potential candidate genes, including transforming growth factor β3 (TGFβ3), were identified in the region of interest, but detailed screening failed to identify mutations in the coding regions of any of these [11,12]. In the present issue of Cardiovascular Research, Beffagna et al. [13] report the results of further investigations searching for mutations in the non-coding region of the TGFβ3 gene in AVRD1 kindreds. In one family, a mutation in the 5'-untranslated region (UTR) was identified. The mutation was found in all nine members of the kindred with proven ARVD, and was also present in three of over 40 asymptomatic members. An unrelated proband was found to have a mutation in the 3'-UTR. Extensive sequencing failed to identify mutations in the TGFβ3 gene in two other kindreds with the same ARVD1 linkage pattern. Both the 5'- and 3'-UTR mutations were found to increase luciferase reporter activity by about 2.5-fold, and neither mutation was found in 300 control patients (600 chromosomes).

The results of this study are intriguing. They clearly suggest that TGFβ3 overexpression resulting from a regulatory site mutation produces ARVD1. This is an extremely interesting finding, with potentially major significance for our understanding of the pathophysiology of ARVD and of the function of TGFβ3. However, a number of issues need to be resolved before TGFβ3 overexpression can be accepted as the molecular basis of ARVD1: (1) The lack of mutations identified in the TGFβ3 gene in two kindreds with typical ARVD1 linkage is of concern. It may be that the mutation lies in a linked site outside the TGFβ3 locus that nevertheless regulates TGFβ3 expression. Another possibility is that there is another gene closely linked to TGFβ3 that is mutated in these kindreds without identified TGFβ3 mutations and causes ARVD. Still another possibility is that the TGFβ3 mutations identified by Beffagna et al. are not causal for AVRD, but are closely linked to another mutated gene that causes ARVD. (2) Confirmation of in vivo overexpression of TGFβ3 in the mutation carriers is not available. Demonstration of TGFβ3 overexpression in cardiac biopsy samples from affected patients would be helpful in confirming the functional relevance of the in vitro promoter studies. (3) The biological connection between TGFβ3 overexpression and ARVD remains to be established.

TGFβ3 is a member of the TGFβ family, which consists of multifunctional cytokines with widespread distribution. Targeted deletion of TGFβ1 results in extensive, eventually lethal inflammation ~3 weeks after birth, whereas TGFβ2 and TGFβ3 mutations cause perinatal death [14]. TGFβ3 ablation impairs palatogenesis and delays pulmonary development, with the Alk-5/Smad2 pathway playing a key role in TGFβ3-driven palatal fusion [15]. TGFβ3 is also involved in trophoblastic [16] and cardiac valve [17] development. Beffagna et al. argue for a role of TGFβ3-induced fibrosis in AVRD. TGFβ3 overexpression has been detected in the skin of patients with scleroderma and implicated in increased collagen production [18]. However, TGFβ3 antagonizes TGFβ1-induced extracellular matrix (ECM) production by fibroblasts [19] and suppresses TGFβ1-induced scar formation in cutaneous wounds [20]. Interestingly, TGFβ3 appears to reduce the production of a variety of tight-junction integral membrane proteins in Sertoli cells, including occludin, zona occludens-1, and claudin-11 [21], by a p38 mitogen-activated protein kinase pathway [22]. It is conceivable that ECM or tight-junction modulation by TGFβ3 is pathogenic in ARVD1, but this possibility remains speculative for the moment. Given the widespread tissue expression of TGFβ3, the apparently quite selective cardiac phenotype of AVRD1 requires explanation. Further work, particularly in genetically engineered models of TGFβ3 overexpression, would be of great interest.

Despite the many questions that remain to be answered, the results reported by Beffagna et al. have the potential to lead to many important new discoveries about the molecular basis of ARVD1 and the biological function of TGFβ3. We look forward to the further unfolding of this fascinating story with great interest. The continuing development of insights into genetic causes of sudden cardiac death promises to provide not only new insights into cardiac physiology and pathophysiology, but potential new approaches to the diagnosis, prevention, and therapy of the conditions underlying this important public health problem [23,24].


   Acknowledgements
 
Supported by the Canadian Institutes of Health Research and the Quebec Heart and Stroke Foundation.


   References
Top
 References
 

  1. Corrado D., Basso C., Thiene G. Sudden cardiac death in young people with apparently normal heart. Cardiovasc. Res. (2001) 50:399–408.[Abstract/Free Full Text]
  2. Paul M., Schulze-Bahr E., Breithardt G., Wichter T. Genetics of arrhythmogenic right ventricular cardiomyopathy–status quo and future perspectives. Z. Kardiol. (2003) 92:128–136.[CrossRef][Web of Science][Medline]
  3. Dalla Volta S., Battaglia G., Zerbini E. "Auricularization" of right ventricular pressure curve. Am. Heart J. (1961) 61:25–33.[CrossRef][Web of Science][Medline]
  4. Nava A., Thiene G., Canciani B., Scognamiglio R., Daliento L., Buja G., et al. Familial occurrence of right ventricular dysplasia: a study involving nine families. J. Am. Coll. Cardiol. (1988) 12:1222–1228.[Abstract]
  5. Tiso N., Stephan D.A., Nava A., Bagattin A., Devaney J.M., Stanchi F., et al. Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2). Hum. Mol. Genet. (2001) 10:189–194.[Abstract/Free Full Text]
  6. McKoy G., Protonotarios N., Crosby A., Tsatsopoulou A., Anastasakis A., Coonar A., et al. Identification of a deletion in plakoglobin in arrhythmogenic right ventricular cardiomyopathy with palmoplantar keratoderma and woolly hair (Naxos disease). Lancet (2000) 355:2119–2124.[CrossRef][Web of Science][Medline]
  7. Norgett E.E., Hatsell S.J., Carvajal-Huerta L., Cabezas J.C., Common J., Purkis P.E., et al. Recessive mutation in desmoplakin disrupts desmoplakin-intermediate filament interactions and causes dilated cardiomyopathy, woolly hair and keratoderma. Hum. Mol. Genet. (2000) 9:2761–2766.[Abstract/Free Full Text]
  8. Rampazzo A., Nava A., Malacrida S., Beffagna G., Bauce B., Rossi V., et al. Mutation in human desmoplakin domain binding to plakoglobin causes a dominant form of arrhythmogenic right ventricular cardiomyopathy. Am. J. Hum. Genet. (2002) 71:1200–1206.[CrossRef][Web of Science][Medline]
  9. Gerull B., Heuser A., Wichter T., Paul M., Basson C.T., McDermott D.A., et al. Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy. Nat. Genet. (2004) 36:1162–1164.[CrossRef][Web of Science][Medline]
  10. Rampazzo A., Nava A., Danieli G.A., Buja G., Daliento L., Fasoli G., et al. The gene for arrhythmogenic right ventricular cardiomyopathy maps to chromosome 14q23–q24. Hum. Mol. Genet. (1994) 3:959–962.[Abstract/Free Full Text]
  11. Rampazzo A., Beffagna G., Nava A., Occhi G., Bauce B., Noiato M., et al. Arrhythmogenic right ventricular cardiomyopathy type 1 (ARVD1): confirmation of locus assignment and mutation screening of four candidate genes. Eur. J. Hum. Genet. (2003) 11:69–76.[CrossRef][Web of Science][Medline]
  12. Rossi V., Beffagna G., Rampazzo A., Bauce B., Danieli G.A. TAIL1: an isthmin-like gene, containing type 1 thrombospondin-repeat and AMOP domain, mapped to ARVD1 critical region. Gene (2004) 335:101–108.[CrossRef][Web of Science][Medline]
  13. Beffagna G., Occhi G., Nava A., Vitiello L., Ditadi A., Basso C., et al. Regulatory mutations in transforming growth factor-β3 gene cause arrhythmogenic right ventricular cardiomyopathy type 1. Cardiovasc. Res. (2005) 65:366–373.[Abstract/Free Full Text]
  14. Dunker N., Krieglstein K. Targeted mutations of transforming growth factor-beta genes reveal important roles in mouse development and adult homeostasis. Eur. J. Biochem. (2000) 267(24):6982–6988.[Web of Science][Medline]
  15. Dudas M., Nagy A., Laping N.J., Moustakas A., Kaartinen V. Tgf-beta3-induced palatal fusion is mediated by Alk-5/Smad pathway. Dev. Biol. (2004) 266:96–108.[CrossRef][Web of Science][Medline]
  16. Nishi H., Nakada T., Hokamura M., Osakabe Y., Itokazu O., Huang L.E., et al. Hypoxia-inducible factor-1 transactivates transforming growth factor-beta3 in trophoblast. Endocrinology (2004) 145:4113–4118.[Abstract/Free Full Text]
  17. Krishnan S., Deora A.B., Annes J.P., Osoria J., Rifkin D.B., Hajjar K.A. Annexin II-mediated plasmin generation activates TGF-beta3 during epithelial–mesenchymal transformation in the developing avian heart. Dev. Biol. (2004) 265:140–154.[CrossRef][Web of Science][Medline]
  18. Ozbilgin M.K., Inan S. The roles of transforming growth factor type beta3 (TGF-beta3) and mast cells in the pathogenesis of scleroderma. Clin. Rheumatol. (2003) 22:189–195.[CrossRef][Web of Science][Medline]
  19. Murata H., Zhou L., Ochoa S., Hasan A., Badiavas E., Falanga V. TGF-beta3 stimulates and regulates collagen synthesis through TGF-beta1-dependent and independent mechanisms. J. Invest. Dermatol. (1997) 108:258–262.[CrossRef][Web of Science][Medline]
  20. Shah M., Foreman D.M., Ferguson M.W. Neutralization of TGF-beta 1 and TGF-beta 2 or exogenous addition of TGF-beta 3 to cutaneous rat wounds reduces scarring. Cell Sci. (1995) 108:985–1002.[Abstract]
  21. Lui W.Y., Lee W.M., Cheng C.Y. Transforming growth factor-beta3 perturbs the inter-Sertoli tight junction permeability barrier in vitro possibly mediated via its effects on occludin, zonula occludens-1, and claudin-11. Endocrinology (2001) 142:1865–1877.[Abstract/Free Full Text]
  22. Lui W.Y., Wong C.H., Mruk D.D., Cheng C.Y. TGF-beta3 regulates the blood–testis barrier dynamics via the p38 mitogen activated protein (MAP) kinase pathway: an in vivo study. Endocrinology (2003) 144:1139–1142.[Abstract/Free Full Text]
  23. Myerburg R.J., Spooner P.M. Opportunities for sudden death prevention: directions for new clinical and basic research. Cardiovasc. Res. (2001) 50:177–185.[Abstract/Free Full Text]
  24. Priori S.G., Napolitano C., Grillo M. Concealed arrhythmogenic syndromes: the hidden substrate of idiopathic ventricular fibrillation? Cardiovasc. Res. (2001) 50:218–223.[Abstract/Free Full Text]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 J Am Coll CardiolHome page
S. Sen-Chowdhry, P. Syrris, and W. J. McKenna
Role of Genetic Analysis in the Management of Patients With Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy
J. Am. Coll. Cardiol., November 6, 2007; 50(19): 1813 - 1821.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Extract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Nattel, S.
Right arrow Articles by Schott, J.-J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Nattel, S.
Right arrow Articles by Schott, J.-J.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?