Contribuição dos polimorfismos no gene FMO3 na patologia e na farmacogenética

  • Laura Teixeira Vilarinho Instituto Nacional de Saúde Doutor Ricardo Jorge, I.P. Unidade de Rastreio Neonatal, Metabolismo e Genética RuaAlexandre Herculano, 321 4000-055 Porto Portugal
  • F. Ferreira
  • L. Almeida
  • C. da Costa
  • P. Janeiro
  • A. Bandeira
  • E. Martins
  • E. Teles
  • P. Garcia
  • L. Azevedo
Palavras-chave: Palavras-chave, Trimetilaminúria, Síndroma de odor a peixe, Flavina mono-oxigenase 3, FMO3, Polimorfismos genéticos, Farmacogenética.

Resumo

O Síndroma de odor a peixe ou trimetilaminúria (TMAu) é uma doença genética de transmissão autossómica recessiva que se manifesta por um forte odor corporal a peixe, devido à incapacidade de conversão do composto odorífero trimetilamina em N-óxido de trimetilamina (composto não odorífero), pela enzima flavina mono-oxigenase 3 (FMO3). Assim, os indivíduos afetados por esta patologia apresentam um odor a peixe em todos os fluidos corporais e, apesar desta doença estar classificada como benigna, os indivíduos afetados apresentam graves problemas psicossociais, afetivos e profissionais. Apesar de ser considerada uma doença rara, esta patologia poderá estar subestimada, pois é frequentemente estudada na criança, mas afeta também indivíduos em idade adulta. Outro fator relevante a considerar no estudo da trimetilaminúriua, é não só a sua contribuição para o conhecimento do espectro mutacional de FMO3, mas salientar a importância que tem a variabilidade inter-individual e intra-individual da expressão da proteína, na metabolização hepática de uma grande maioria de fármacos.

Neste trabalho, pretendeu-se dar a conhecer o espetro mutacional para a TMAu em doentes Portugueses tendo sido estudados 52 doentes com fenótipo sugestivo de TMAu.

Nos 52 doentes estudados com fenótipo sugestivo de TMAu foi confirmada a presença de polimorfismos e/ou mutações patogénicas no gene FMO3, tendo-se observado 32 variantes. Verificou-se que a presença dos polimorfismos p.Glu158Lys e p.Glu308Gly, em combinação com outras variantes, originavam padrões diferentes no fenótipo, essencialmente em cis ou quando presentes em homozigotia.

Com os resultados obtidos correlacionou-se o genótipo da doença com o fenótipo, alertando-se para a necessidade do estudo desta patologia de uma forma integrada com a farmacogenética uma vez que o estudo mutacional deste gene poderá num futuro próximo ser encarado como uma possível ferramenta, na previsibilidade do sucesso de actuação de um determinado fármaco que sirva de substrato à enzima FMO3.

Deste estudo salientamos a necessidade de clarificar não só a patogeneicidade das novas variantes encontradas, bem como dos seus efeitos na atividade enzimática de FMO3. Por outro lado, pretendemos também avaliar qual o papel que desempenham os polimorfismos mais comuns no binómio genótipo/fenótipo e/ou mecanismo protetor relativamente às drogas xenobióticas ou ambientais.

 

Biografia Autor

Laura Teixeira Vilarinho, Instituto Nacional de Saúde Doutor Ricardo Jorge, I.P. Unidade de Rastreio Neonatal, Metabolismo e Genética RuaAlexandre Herculano, 321 4000-055 Porto Portugal

Departamento de Genética Humana

Unidade de Rastreio Neonatal, Metabolismo e Genética

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Publicado
2015-11-14
Secção
Artigos