title: Regulatory mutations in transforming growth factor-beta3 gene cause arrhythmogenic right ventricular cardiomyopathy type 1.
abstract: 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.
  
  
  RESULTS
  Mutation screening of the promoter and untranslated regions (UTRs) of the transforming growth factor-beta3 (TGFbeta3) 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 TGFbeta3 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.
  
  
  CONCLUSIONS
  We identified TGFbeta3 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.
authors.affiliation: Department of Biology, University of Padua, Via Ugo Bassi 58/B 35131 Padua, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Beffagna
authors.forename: Gianluca
authors.initials: G
authors.lastname: Occhi
authors.forename: Andrea
authors.initials: A
authors.lastname: Nava
authors.forename: Libero
authors.initials: L
authors.lastname: Vitiello
authors.forename: Andrea
authors.initials: A
authors.lastname: Ditadi
authors.forename: Cristina
authors.initials: C
authors.lastname: Basso
authors.forename: Barbara
authors.initials: B
authors.lastname: Bauce
authors.forename: Gianni
authors.initials: G
authors.lastname: Carraro
authors.forename: Gaetano
authors.initials: G
authors.lastname: Thiene
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Towbin
authors.forename: Gian Antonio
authors.initials: GA
authors.lastname: Danieli
authors.forename: Alessandra
authors.initials: A
authors.lastname: Rampazzo
mesh_terms: D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D000818:Animals; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D002478:Cells, Cultured; D002648:Child; D002851:Chromatography, High Pressure Liquid; D004252:DNA Mutational Analysis; D016757:Death, Sudden, Cardiac / Q000209:etiology; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D051379:Mice; D032383:Myocytes, Cardiac; D010375:Pedigree; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D053782:Transforming Growth Factor beta3
chemical_list: D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; C509045:Tgfb3 protein, mouse; D016212:Transforming Growth Factor beta; D053782:Transforming Growth Factor beta3