Análise da correlação genótipo-fenótipo na homocistinúria

• Ano de defesa: 2016
• Autor(a) principal: Silva, Jose Araujo de Oliveira [UNIFESP]
• Tipo de documento: Dissertação
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal de São Paulo (UNIFESP)
• Palavras-chave em Português: Erro inato do metabolismo; Homocistinúria; Genótipo; Fenótipo; Gene cbs; Cistationina; Sintase
• Link de acesso: https://sucupira.capes.gov.br/sucupira/public/consultas/coleta/trabalhoConclusao/viewTrabalhoConclusao.jsf?popup=true&id_trabalho=3771527; http://repositorio.unifesp.br/handle/11600/46219

Classical homocystinuria is an inborn error of metabolism (IEM), autosomal recessive and caused by a deficiency of the enzyme cystathionine ?-synthase (CBS) whose function is to convert the amino acid methionine to cysteine. The CBS gene is located on chromosome 21q22.3, and currently are more than 180 mutations described. The enzyme deficiency results in the elevated plasma levels of homocysteine and methionine, decreased levels of cysteine, and the most common clinical manifestations are: ocular diseases, lens luxation being the most frequent, mental retardation, psychiatric disorders, deformities skeletal such as scoliosis and vascular problems, which is the most common cause of morbidity and mortality in patients with homocystinuria. The aim of this project was carried out molecular diagnosis and correlate genotype with phenotype in patients with clinical diagnosis of classical homocystinuria. Result: the molecular analysis of 20 patients (18 uncorrelated) resulted in nine mutations; seven pathogenic and described as causing classical homocystinuria and two undescribed (G351R and L364V). The most prevalent in this sample was G151R in five patients (one with heterozygous L364V), then with three each respectively: R379W; T191M; W323X. The I278T and T353M mutations present in two patients each; the E302K, G351R and L364V mutations were observed in only one patient each one. We did not find the G307S this population. Most mutations in the affected allele were found in homozygous (80%). The mutations I278T, T191M, W323X, E302K, G151R described in the literature did not have the same frequency in our sample, but the same genotype and phenotype correlations were observed (mild to moderate). The G351R and E302K mutations confer a phenotype of nonresponsiveness to vitamin B6. Patients with W379W and T353M mutations had moderate phenotype, which differ from the literature. The new G351 mutation was classified as severe and L364V moderate. Conclusion: Our article is the first to associate genotype and phenotype in patients with homocystinuria in Brazil. However, despite our pioneering, we must be careful with some particular aspects of the sample, such as the small number of patients analyzed and high rates of miscegenation of the Brazilian population. The genotype and phenotype correlation is complex and depends on numerous factors such as the establishment of criteria for the classification of the phenotype; age at diagnosis; adherence to treatment; mutations well described and prevalent in countries with miscegenation. So there is need for further studies so that we can correlate more reliably genotype to phenotype these patients.