Copyright © 2004, European Society of Cardiology
Regulatory mutations in transforming growth factor-β3 gene cause arrhythmogenic right ventricular cardiomyopathy type 1
aDepartment of Biology, University of Padua, Via Ugo Bassi 58/B 35131 Padua, Italy
bDepartment of Cardiology, University of Padua, 35131 Padua, Italy
cInstitute of Pathology, University of Padua, 35131 Padua, Italy
dDepartment of Human Anatomy, University of Padua, 35131 Padua, Italy
eDepartment of Pediatrics, Section of Cardiology, Baylor College of Medicine, Houston, USA
* Corresponding author. Tel.: +39 49 8276208; fax: +39 49 8276209. Email address: alessandra.rampazzo{at}unipd.it
Objective: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically heterogeneous disorder characterized by fibro-fatty replacement of the right ventricular myocardium, associated with high risk of sudden death. The objective of this study is to identify the gene involved in ARVD1, which has been elusive ever since its locus was mapped to chromosome 14q24.3.
Methods and results: Mutation screening of the promoter and untranslated regions (UTRs) of the transforming growth factor-beta3 (TGFβ3) gene was performed by direct sequencing of genomic DNA of one index case belonging to an ARVD1 family including 38 members in four generations. We detected a nucleotide substitution (c.–36G>A) in 5' UTR of TGFβ3 gene, invariably associated with the typical ARVC clinical phenotype in the affected family members, according to the established diagnostic criteria. Investigation extended to 30 unrelated ARVC patients, performed by denaturing high-performance liquid chromatography (DHPLC), led to the identification of an additional mutation (c.1723C>T) in the 3' UTR of one proband. Neither nucleotide change was found in 300 control subjects. In vitro expression assays with constructs containing the mutations showed that mutated UTRs were twofold more active than wild-types.
Conclusion: We identified TGFβ3 as the disease gene involved in ARVD1. The identification of a novel ARVC gene will increase the power of the genetic screening for early diagnosis of asymptomatic carriers among relatives of ARVC patients.
KEYWORDS Gene expression; Cardiomyopathy; Sudden death; Ventricular arrhythmias
1 These authors equally contributed to this work.
Time for primary review 12 days
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  B. Ozben, I. Altun, V. Sabri Hancer, A. K. Bilge, A. M. Tanrikulu, R. Diz-Kucukkaya, A. S. Fak, E. Yilmaz, and K. Adalet Angiotensin-converting enzyme gene polymorphism in arrhythmogenic right ventricular dysplasia: is DD genotype helpful in predicting syncope risk? Journal of Renin-Angiotensin-Aldosterone System, December 1, 2008; 9(4): 215 - 220. [Abstract] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
N. H. Robin, P. B. Tabereaux, R. Benza, and B. R. Korf Genetic Testing in Cardiovascular Disease J. Am. Coll. Cardiol., August 21, 2007; 50(8): 727 - 737. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Moric-Janiszewska and G. Markiewicz-Loskot Review on the genetics of arrhythmogenic right ventricular dysplasia Europace, May 1, 2007; 9(5): 259 - 266. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Avila, I. M. Medina, E. Jimenez, G. Elizondo, and C. I. Aguilar Transforming growth factor-beta1 decreases cardiac muscle L-type Ca2+ current and charge movement by acting on the Cav1.2 mRNA Am J Physiol Heart Circ Physiol, January 1, 2007; 292(1): H622 - H631. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Dalal, C. James, R. Devanagondi, C. Tichnell, A. Tucker, K. Prakasa, P. J. Spevak, D. A. Bluemke, T. Abraham, S. D. Russell, et al. Penetrance of Mutations in Plakophilin-2 Among Families With Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy J. Am. Coll. Cardiol., October 3, 2006; 48(7): 1416 - 1424. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Yang, N. E. Bowles, S. E. Scherer, M. D. Taylor, D. L. Kearney, S. Ge, V. V. Nadvoretskiy, G. DeFreitas, B. Carabello, L. I. Brandon, et al. Desmosomal Dysfunction due to Mutations in Desmoplakin Causes Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Circ. Res., September 15, 2006; 99(6): 646 - 655. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Basso, E. Czarnowska, M. D. Barbera, B. Bauce, G. Beffagna, E. K. Wlodarska, K. Pilichou, A. Ramondo, A. Lorenzon, O. Wozniek, et al. Ultrastructural evidence of intercalated disc remodelling in arrhythmogenic right ventricular cardiomyopathy: an electron microscopy investigation on endomyocardial biopsies Eur. Heart J., August 1, 2006; 27(15): 1847 - 1854. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Dalal, L. H. Molin, J. Piccini, C. Tichnell, C. James, C. Bomma, K. Prakasa, J. A. Towbin, F. I. Marcus, P. J. Spevak, et al. Clinical Features of Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Associated With Mutations in Plakophilin-2 Circulation, April 4, 2006; 113(13): 1641 - 1649. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.P. van Tintelen, M. M. Entius, Z. A. Bhuiyan, R. Jongbloed, A. C.P. Wiesfeld, A. A.M. Wilde, J. van der Smagt, L. G. Boven, M. M.A.M. Mannens, I. M. van Langen, et al. Plakophilin-2 Mutations Are the Major Determinant of Familial Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Circulation, April 4, 2006; 113(13): 1650 - 1658. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Pilichou, A. Nava, C. Basso, G. Beffagna, B. Bauce, A. Lorenzon, G. Frigo, A. Vettori, M. Valente, J. Towbin, et al. Mutations in Desmoglein-2 Gene Are Associated With Arrhythmogenic Right Ventricular Cardiomyopathy Circulation, March 7, 2006; 113(9): 1171 - 1179. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Syrris, D. Ward, A. Asimaki, S. Sen-Chowdhry, H. Y. Ebrahim, A. Evans, N. Hitomi, M. Norman, A. Pantazis, A. L. Shaw, et al. Clinical Expression of Plakophilin-2 Mutations in Familial Arrhythmogenic Right Ventricular Cardiomyopathy Circulation, January 24, 2006; 113(3): 356 - 364. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Bauce, C. Basso, A. Rampazzo, G. Beffagna, L. Daliento, G. Frigo, S. Malacrida, L. Settimo, G. Danieli, G. Thiene, et al. Clinical profile of four families with arrhythmogenic right ventricular cardiomyopathy caused by dominant desmoplakin mutations Eur. Heart J., August 2, 2005; 26(16): 1666 - 1675. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Corrado, C. Basso, L. Leoni, B. Tokajuk, B. Bauce, G. Frigo, G. Tarantini, M. Napodano, P. Turrini, A. Ramondo, et al. Three-Dimensional Electroanatomic Voltage Mapping Increases Accuracy of Diagnosing Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia Circulation, June 14, 2005; 111(23): 3042 - 3050. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Nattel and J.-J. Schott Arrhythmogenic right ventricular dysplasia type 1 and mutations in transforming growth factor {beta}3 gene regulatory regions: a breakthrough? Cardiovasc Res, February 1, 2005; 65(2): 302 - 304. [Full Text] [PDF]
|
|