Análise da correlação genótipo-fenótipo na homocistinúria

Detalhes bibliográficos
Autor(a) principal: Silva, Jose Araujo de Oliveira [UNIFESP]
Data de Publicação: 2016
Tipo de documento: Dissertação
Idioma: por
Título da fonte: Repositório Institucional da UNIFESP
dARK ID: ark:/48912/001300000jj44
Texto Completo: https://sucupira.capes.gov.br/sucupira/public/consultas/coleta/trabalhoConclusao/viewTrabalhoConclusao.jsf?popup=true&id_trabalho=3771527
http://repositorio.unifesp.br/handle/11600/46219
Resumo: 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.
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spelling Análise da correlação genótipo-fenótipo na homocistinúriaAnalysis of the correlation genotype-phenotype in homocystinuriaErro inato do metabolismoHomocistinúriaGenótipoFenótipoGene cbsCistationinaSintaseClassical 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.A homocistinúria clássica é um erro inato do metabolismo (EIM), de herança autossômica recessiva e causada pela deficiência da enzima cistationina ?-sintase (CBS), cuja função é converter o aminoácido metionina em cisteína. O gene que codifica a CBS está localizado no cromossomo 21q22.3, sendo que atualmente estão descritas mais de 180 mutações relacionadas à homocistinúria. A deficiência enzimática tem como consequência a elevação dos níveis plasmáticos da homocisteína e da metionina, diminuição dos níveis da cisteína, e as manifestações clínicas associadas mais frequentes são: alterações oculares, sendo a luxação do cristalino a mais frequente, retardo mental, alterações psiquiátricas, deformidades esqueléticas como escoliose e problemas vasculares, sendo esta a causa mais comum de morbidade e mortalidade em pacientes com homocistinúria. O objetivo deste projeto foi padronizar e realizar o diagnóstico molecular em pacientes com diagnóstico clínico de homocistinúria clássica e tentar estabelecer uma correlação entre o genótipo e o fenótipo nesses pacientes. Resultado: a análise molecular dos 20 pacientes (18 não correlacionados) resultou na determinação de nove mutações, dentre elas sete patogênicas e descritas como causadoras da homocistinúria clássica e duas não descritas (G351R e L364V). A mutação mais prevalente nesta amostra foi a G151R, encontrada em cinco pacientes (um deles em heterozigose composta com a L364V), seguida das mutações T191M, W323X e R379W, as quais foram encontradas cada uma em três pacientes. As mutações I278T e T353M apresentaram-se em dois pacientes cada uma e as mutações E302K, G351R e L364V foram observadas em apenas um paciente cada. A maioria das mutações foi encontrada em homozigose (80%). Os pacientes com as mutações G151R, T191M, I278T, W323X e E302K apresentaram as mesmas correlações genótipo e fenótipo observadas na literatura (leve e moderada). As mutações G351R e E302K conferiram um fenótipo de não responsividade à vitamina B6. Os pacientes com as mutações W379W e T353M apresentaram fenótipo moderado, o que diferiu dos dados da literatura. A nova mutação G351 foi classificada como grave e a L364V moderada. Conclusão: O nosso trabalho é o primeiro a relacionar o genótipo e fenótipo em pacientes com homocistinúria no Brasil. Entretanto, apesar de nosso pioneirismo, devemos ter cuidado com alguns aspectos particulares dessa amostra, tais como o pequeno número de pacientes analisados e altos índices de miscigenação da população brasileira. A correlação do genótipo e fenótipo é complexa e depende de inúmeros fatores tais como a criação de critérios para a classificação do fenótipo; a idade do diagnóstico; a adesão do paciente ao tratamento; mutações bem descritas e prevalentes em outros países com miscigenação. Portanto, há necessidade de mais estudos para que possamos correlacionar de forma mais fidedigna o genótipo ao fenótipo destes pacientes.Dados abertos - Sucupira - Teses e dissertações (2013 a 2016)Universidade Federal de São Paulo (UNIFESP)Pesquero, Joao Bosco [UNIFESP]http://lattes.cnpq.br/0856630824759511http://lattes.cnpq.br/2616407175329759Universidade Federal de São Paulo (UNIFESP)Silva, Jose Araujo de Oliveira [UNIFESP]2018-07-27T15:49:47Z2018-07-27T15:49:47Z2016-09-30info:eu-repo/semantics/masterThesisinfo:eu-repo/semantics/publishedVersion77 f.application/pdfhttps://sucupira.capes.gov.br/sucupira/public/consultas/coleta/trabalhoConclusao/viewTrabalhoConclusao.jsf?popup=true&id_trabalho=3771527SILVA, Jose Araujo de Oliveira. Análise da correlação genótipo-fenótipo na homocistinúria. 2016. 77 f. Dissertação (Mestrado em Ciências Biológicas: Biologia Molecular) - Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo, 2016.2016-0138.pdfhttp://repositorio.unifesp.br/handle/11600/46219ark:/48912/001300000jj44porSão Pauloinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UNIFESPinstname:Universidade Federal de São Paulo (UNIFESP)instacron:UNIFESP2024-08-11T05:05:46Zoai:repositorio.unifesp.br/:11600/46219Repositório InstitucionalPUBhttp://www.repositorio.unifesp.br/oai/requestbiblioteca.csp@unifesp.bropendoar:34652024-12-11T20:21:14.604121Repositório Institucional da UNIFESP - Universidade Federal de São Paulo (UNIFESP)false
dc.title.none.fl_str_mv Análise da correlação genótipo-fenótipo na homocistinúria
Analysis of the correlation genotype-phenotype in homocystinuria
title Análise da correlação genótipo-fenótipo na homocistinúria
spellingShingle Análise da correlação genótipo-fenótipo na homocistinúria
Silva, Jose Araujo de Oliveira [UNIFESP]
Erro inato do metabolismo
Homocistinúria
Genótipo
Fenótipo
Gene cbs
Cistationina
Sintase
title_short Análise da correlação genótipo-fenótipo na homocistinúria
title_full Análise da correlação genótipo-fenótipo na homocistinúria
title_fullStr Análise da correlação genótipo-fenótipo na homocistinúria
title_full_unstemmed Análise da correlação genótipo-fenótipo na homocistinúria
title_sort Análise da correlação genótipo-fenótipo na homocistinúria
author Silva, Jose Araujo de Oliveira [UNIFESP]
author_facet Silva, Jose Araujo de Oliveira [UNIFESP]
author_role author
dc.contributor.none.fl_str_mv Pesquero, Joao Bosco [UNIFESP]
http://lattes.cnpq.br/0856630824759511
http://lattes.cnpq.br/2616407175329759
Universidade Federal de São Paulo (UNIFESP)
dc.contributor.author.fl_str_mv Silva, Jose Araujo de Oliveira [UNIFESP]
dc.subject.por.fl_str_mv Erro inato do metabolismo
Homocistinúria
Genótipo
Fenótipo
Gene cbs
Cistationina
Sintase
topic Erro inato do metabolismo
Homocistinúria
Genótipo
Fenótipo
Gene cbs
Cistationina
Sintase
description 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.
publishDate 2016
dc.date.none.fl_str_mv 2016-09-30
2018-07-27T15:49:47Z
2018-07-27T15:49:47Z
dc.type.driver.fl_str_mv info:eu-repo/semantics/masterThesis
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
format masterThesis
status_str publishedVersion
dc.identifier.uri.fl_str_mv https://sucupira.capes.gov.br/sucupira/public/consultas/coleta/trabalhoConclusao/viewTrabalhoConclusao.jsf?popup=true&id_trabalho=3771527
SILVA, Jose Araujo de Oliveira. Análise da correlação genótipo-fenótipo na homocistinúria. 2016. 77 f. Dissertação (Mestrado em Ciências Biológicas: Biologia Molecular) - Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo, 2016.
2016-0138.pdf
http://repositorio.unifesp.br/handle/11600/46219
dc.identifier.dark.fl_str_mv ark:/48912/001300000jj44
url https://sucupira.capes.gov.br/sucupira/public/consultas/coleta/trabalhoConclusao/viewTrabalhoConclusao.jsf?popup=true&id_trabalho=3771527
http://repositorio.unifesp.br/handle/11600/46219
identifier_str_mv SILVA, Jose Araujo de Oliveira. Análise da correlação genótipo-fenótipo na homocistinúria. 2016. 77 f. Dissertação (Mestrado em Ciências Biológicas: Biologia Molecular) - Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo, 2016.
2016-0138.pdf
ark:/48912/001300000jj44
dc.language.iso.fl_str_mv por
language por
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 77 f.
application/pdf
dc.coverage.none.fl_str_mv São Paulo
dc.publisher.none.fl_str_mv Universidade Federal de São Paulo (UNIFESP)
publisher.none.fl_str_mv Universidade Federal de São Paulo (UNIFESP)
dc.source.none.fl_str_mv reponame:Repositório Institucional da UNIFESP
instname:Universidade Federal de São Paulo (UNIFESP)
instacron:UNIFESP
instname_str Universidade Federal de São Paulo (UNIFESP)
instacron_str UNIFESP
institution UNIFESP
reponame_str Repositório Institucional da UNIFESP
collection Repositório Institucional da UNIFESP
repository.name.fl_str_mv Repositório Institucional da UNIFESP - Universidade Federal de São Paulo (UNIFESP)
repository.mail.fl_str_mv biblioteca.csp@unifesp.br
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