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
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