Mutations in the untranslated regions of the TGFbeta3 gene were identified as the cause of ARVD1, with mutated constructs showing twofold higher in vitro activity than wild-types.
Case-Control (n=368)
Are regulatory mutations in the transforming growth factor-beta3 (TGFbeta3) gene associated with arrhythmogenic right ventricular cardiomyopathy type 1 (ARVD1)?
The identification of TGFbeta3 as the disease gene for ARVD1 provides a novel target for genetic screening and early diagnosis of asymptomatic carriers in affected families.
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 (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. CONCLUSION: 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.
Beffagna et al. (Wed,) conducted a case-control in Arrhythmogenic right ventricular cardiomyopathy type 1 (ARVD1) (n=368). Mutation screening of TGFbeta3 gene vs. Control subjects (wild-type) was evaluated on Identification of the gene involved in ARVD1. Mutations in the untranslated regions of the TGFbeta3 gene were identified as the cause of ARVD1, with mutated constructs showing twofold higher in vitro activity than wild-types.
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