Novos genes no diagnóstico genético de Miocardiopatia Hipertrófica
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2014
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A Miocardiopatia Hipertrófica (MH) é uma doença genética cardiovascular, ocorrendo em 1/500 indivíduos da população em geral. É considerada a principal causa de morte súbita em jovens e jovens atletas.
A MH apresenta um padrão de transmissão autossómica dominante com elevada variabilidade clínica (mesmo no seio da mesma família) e genética (quer ao nível de locus quer alélica). Esta variabilidade genética influencia a magnitude da hipertrofia cardíaca e o risco de morte súbita.
A maioria das mutações descritas estão associadas a genes que codificam para proteínas sarcoméricas. No entanto em mais de 40% dos pacientes com MH não se encontram mutações em genes conhecidos. Vários estudos recentes associam outros genes não sarcoméricos a casos de MH, como por exemplo, genes que codificam para proteínas envolvidas na sinalização de cálcio e nas funções auxiliares ao sarcómero cujas mutações podem ser responsáveis pelo desenvolvimento de MH, quer como genes de susceptibilidade (ACTN2, FHL1, GLA, RAF1, TTR, VCL) quer como genes modificadores (AGTR1).
Neste trabalho, pretendeu-se aplicar a técnica de HRM ao diagnóstico genético de MH, analisando um grupo de 58 indivíduos, - 39 indivíduos com diagnóstico de MH sem mutações nos principais genes sarcoméricos previamente identificadas, 9 dos quais são atletas de alta competição e 19 jovens atletas sem diagnóstico de MH. Para tal, foram desenhados, optimizados e testados 14 pares de primers para a aplicação em HRM.
Neste trabalho, foi possível detectar as seguintes mutações no gene ACTN2 (IVS7+34G>A, IVS7+80A>G, IVS8+23G>A) e no gene AGTR1, na região 3’UTR 1166A>C, confirmadas por SA.
A técnica de HRM diminuiu drasticamente a necessidade de SA, diminuindo os custos e tempo de espera dos resultados.
Hypertrophic cardiomyopathy (HCM) is a cardiovascular genetic disorder, that occurs in 1/500 individuals in the general population and is rated as the main common cause of sudden dead in young people and young athletes. HCM has an autosomal dominant pattern of transmission, showing a high clinical variability (even in the same family) and genetics (both at locus or allelic level). This genetic variability affects the magnitude of cardiac hypertrophy and risk of sudden death. Most of the described mutations are associated with genes encoding sarcomeric proteins. However more than 40% of index patients, no mutation in known genes is identified. Several recent studies have associated non-sarcomeric genes with HCM cases, such as genes encoding proteins implicated in calcium signalling and auxiliary functions to the sarcomere – whose mutations may guide the development of the HCM -, susceptibility genes like (ACTN2, FHL1, GLA, RAF1, TTR, VCL).and modifiers genes such as (AGTR1). The aim of this work was to apply High Resolution Melting (HRM) technique in HCM genetic diagnosis, analyzing a group of 58 individuals- 39 with HCM, without previously identified mutations in the key sarcomeric genes, 9 of them young athletes and 19 healthy young athletes Therefore, 14 primer pairs were designed, optimized and tested for their use in HRM. With this study it was possible to detect the following modifications in the ACTN2 gene: IVS7+34G>A, IVS7+80A>G, IVS8+23G>A; and in the AGTR1 gene: 3’UTR 1166A>C of, confirmed by SA. The HRM technique drastically reduced the need of SA, decreasing both costs and time period for results.
Hypertrophic cardiomyopathy (HCM) is a cardiovascular genetic disorder, that occurs in 1/500 individuals in the general population and is rated as the main common cause of sudden dead in young people and young athletes. HCM has an autosomal dominant pattern of transmission, showing a high clinical variability (even in the same family) and genetics (both at locus or allelic level). This genetic variability affects the magnitude of cardiac hypertrophy and risk of sudden death. Most of the described mutations are associated with genes encoding sarcomeric proteins. However more than 40% of index patients, no mutation in known genes is identified. Several recent studies have associated non-sarcomeric genes with HCM cases, such as genes encoding proteins implicated in calcium signalling and auxiliary functions to the sarcomere – whose mutations may guide the development of the HCM -, susceptibility genes like (ACTN2, FHL1, GLA, RAF1, TTR, VCL).and modifiers genes such as (AGTR1). The aim of this work was to apply High Resolution Melting (HRM) technique in HCM genetic diagnosis, analyzing a group of 58 individuals- 39 with HCM, without previously identified mutations in the key sarcomeric genes, 9 of them young athletes and 19 healthy young athletes Therefore, 14 primer pairs were designed, optimized and tested for their use in HRM. With this study it was possible to detect the following modifications in the ACTN2 gene: IVS7+34G>A, IVS7+80A>G, IVS8+23G>A; and in the AGTR1 gene: 3’UTR 1166A>C of, confirmed by SA. The HRM technique drastically reduced the need of SA, decreasing both costs and time period for results.
Descrição
Orientação: Maria Alexandra Núncio de Carvalho Ramos
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Palavras-chave
ENGENHARIA, ENGENHARIA BIOTECNOLÓGICA, MIOCARDIA HIPERTRÓFICA, DIAGNÓSTICOS, GENES, MUTAÇÕES GENÉTICAS, MESTRADO EM ENGENHARIA BIOTECNOLÓGICA, ENGINEERING, BIOTECHNOLOGY ENGINEERING, HYPERTROPHIC CARDIOMYOPATHY, DIAGNOSES, GENES, GENE MUTATIONS