RESUMO
BACKGROUND: Arrythmogenic Right Ventricular Cardiomyopathy (ARVC) is a primary myocardial disorder morphologically characterized by subtle to severe replacement of the right ventricular myocardium by fatty and fibrous tissue. ARVC is known to be highly prevalent in European population with recent reports implicating it to be a major cause of sudden death in young individuals even from American and Asian population. AIM: To implicate or exclude TMEM43 (ARVC-5), DSP(ARVC-8) genes and the yet to be identified gene at ARVC-6 locus in the pathogenesis in three families affected with ARVC from India. MATERIALS AND METHODS: Three families comprising of 42 affected/unaffected members were included in the study. Three microsatellite markers, D3S3613 (ARVC5) D10S1664 (ARVC6), D6S309 (ARVC8) were genotyped by PCR-based native PAGE. Two-point Linkage analysis was performed using LINKAGE program version 5.2 RESULTS AND DISCUSSION: LOD scores from linkage analysis for the microsatellite marker D10S1664 (ARVC-6) in families KS and REV have shown positive value hinting the involvement of this locus in the etiology of ARVC, while linkage analysis in the SB family ruled out involvement of DSP, TMEM43 and ARVC-6, as negative LOD scores were obtained with all three loci. Therefore, linkage analysis carried out in the present study indicates that ARVC-6 (cumulative LOD score is equal to plus 1.203376 at θ is equal to 0.05) could be the locus harboring the mutated gene in two out of three families.
Assuntos
Adulto , Displasia Arritmogênica Ventricular Direita/diagnóstico , Displasia Arritmogênica Ventricular Direita/etiologia , Displasia Arritmogênica Ventricular Direita/genética , Criança , Morte Súbita Cardíaca/epidemiologia , Morte Súbita Cardíaca/etiologia , Família , Feminino , Ligação Genética/genética , Humanos , Índia/epidemiologia , Escore Lod , Masculino , Repetições de Microssatélites , Mutagênese Insercional/genética , Reação em Cadeia da Polimerase/métodosRESUMO
Objective:To sieve molecular biomarkers associated with heart failure derived from arrhythmogenic right ventricular cardiomyopathy (ARVC).Methods:The comparative gene microarray analysis using individual left ventricular myocardial samples from 5 patients with heart failure resulting from ARVC undergoing transplantation and 5 matched samples from normal adult heart were performed.The accuracy rate of the differentially expressed genes obtained by gene microarray was further verified by quantitative real time RT-PCR.Results:83 genes (from a total of 35000) that were differentially expressed in diseased hearts versus normal hearts were identified.Among them thirty-seven genes were up-regulated and forty-eight genes were down-regulated in ARVC hearts compared with the normal hearts.Changes of gene expressions were most prominently observed in those belonging to the "metabolism" category.Eighty percent of the selected 30 differentially expressed genes from microarray analysis were confirmed by quantitative real time RT-PCR.The highly expressed level of atrial natriuratic peptide (ANP) in ARVC hearts that was confirmed by quantitative real time RT-PCR and immunohistochemistry was reported.Conclusion:For the first time to our knowledge,the altered expressed genes in ARVC hearts compared with the matched normal hearts were identified.The results are the base to further study the molecular mechanism and identify diseased-specific molecular biomarkers in heart failure derived from ARVC.