Regulatory mutations in transforming growth factor-β3 gene cause arrhythmogenic right ventricular cardiomyopathy type 1

Giorgia Beffagna, Gianluca Occhi, Andrea Nava, Libero Vitiello, Andrea Ditadi, Cristina Basso, Barbara Bauce, Gianni Carraro, Gaetano Thiene, Jeffrey A. Towbin, Gian Antonio Danieli, Alessandra Rampazzo

Research output: Contribution to journalArticle

279 Citations (Scopus)

Abstract

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. 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. 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.

Original languageEnglish (US)
Pages (from-to)366-373
Number of pages8
JournalCardiovascular research
Volume65
Issue number2
DOIs
StatePublished - Feb 1 2005

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Arrhythmogenic Right Ventricular Dysplasia
Transforming Growth Factors
Transforming Growth Factor beta3
Mutation
Untranslated Regions
Genes
Nucleotides
5' Untranslated Regions
Genetic Testing
3' Untranslated Regions
Sudden Death
DNA Sequence Analysis
Genetic Promoter Regions
Early Diagnosis
Myocardium
Chromosomes
High Pressure Liquid Chromatography
Arrhythmogenic Right Ventricular Dysplasia, Familial, 1
Phenotype

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Regulatory mutations in transforming growth factor-β3 gene cause arrhythmogenic right ventricular cardiomyopathy type 1. / Beffagna, Giorgia; Occhi, Gianluca; Nava, Andrea; Vitiello, Libero; Ditadi, Andrea; Basso, Cristina; Bauce, Barbara; Carraro, Gianni; Thiene, Gaetano; Towbin, Jeffrey A.; Danieli, Gian Antonio; Rampazzo, Alessandra.

In: Cardiovascular research, Vol. 65, No. 2, 01.02.2005, p. 366-373.

Research output: Contribution to journalArticle

Beffagna, G, Occhi, G, Nava, A, Vitiello, L, Ditadi, A, Basso, C, Bauce, B, Carraro, G, Thiene, G, Towbin, JA, Danieli, GA & Rampazzo, A 2005, 'Regulatory mutations in transforming growth factor-β3 gene cause arrhythmogenic right ventricular cardiomyopathy type 1', Cardiovascular research, vol. 65, no. 2, pp. 366-373. https://doi.org/10.1016/j.cardiores.2004.10.005
Beffagna, Giorgia ; Occhi, Gianluca ; Nava, Andrea ; Vitiello, Libero ; Ditadi, Andrea ; Basso, Cristina ; Bauce, Barbara ; Carraro, Gianni ; Thiene, Gaetano ; Towbin, Jeffrey A. ; Danieli, Gian Antonio ; Rampazzo, Alessandra. / Regulatory mutations in transforming growth factor-β3 gene cause arrhythmogenic right ventricular cardiomyopathy type 1. In: Cardiovascular research. 2005 ; Vol. 65, No. 2. pp. 366-373.
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