Assuntos
Doença de Alzheimer/genética , Hiper-Homocisteinemia/genética , 5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/genética , 5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/metabolismo , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Alelos , Doença de Alzheimer/enzimologia , Doença de Alzheimer/patologia , Apolipoproteína E4 , Apolipoproteínas E/genética , Distribuição de Qui-Quadrado , Cistationina beta-Sintase/genética , Cistationina beta-Sintase/metabolismo , Feminino , Frequência do Gene , Predisposição Genética para Doença/genética , Genótipo , Homocisteína/metabolismo , Humanos , Hiper-Homocisteinemia/metabolismo , Modelos Logísticos , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , Mutação de Sentido Incorreto , Polimorfismo Genético , Fatores Sexuais , Análise de SobrevidaRESUMO
In homocystinuria due to cystathionine beta-synthase (CBS) deficiency, vitamin B6 response has been linked to distinct mutations and ruled out for others. The splice site mutation c.1224-2A>C leading to the deletion of exon 12 is predominantly found in patients from Central Europe, where it has been found on in average 14% of mutant alleles. In this study we analyzed the clinical picture in 17 CBS deficient carriers of c.1224-2A>C. Homozygotes for c.1224-2A>C did not respond to vitamin B6, while in compound heterozygotes the response to vitamin B6 depended on the mutation on the second allele. Maximum likelihood analysis revealed one common haplotype of the c.1224-2A>C alleles. Additionally, we report the four novel CBS mutations c.451G>A (p.Gly151?), c.740_769del (p.Lys247_Gly256del), c.862G>C (p.Ala288Pro) and c.1135C>T (p.Arg379Trp). In summary, the data of this study suggest that the CBS c.1224-2A>C allele confers vitamin B6 nonresponsiveness and that this mutant allele came from a common ancestor.
Assuntos
Cistationina beta-Sintase/genética , Efeito Fundador , Homocistinúria/genética , Sítios de Splice de RNA/genética , Vitamina B 6/uso terapêutico , Alelos , Áustria/etnologia , Cistationina beta-Sintase/fisiologia , Resistência a Medicamentos/genética , Europa Oriental/etnologia , Éxons/genética , Feminino , Genótipo , Alemanha/etnologia , Haplótipos/genética , Homocistinúria/tratamento farmacológico , Homocistinúria/etnologia , Humanos , Judeus/genética , Funções Verossimilhança , Masculino , Mutação de Sentido Incorreto , Deleção de Sequência , Turquia/etnologia , Vitamina B 6/farmacologiaRESUMO
Argininosuccinic aciduria is an urea cycle disorder caused by argininosuccinate lyase (ASL) deficiency and is inherited as an autosomal-recessive trait. To date, mutation analysis has been limited because of incomplete sequence information about the human ASL gene. As a consequence, only 12 different mutations in 12 patients have been reported, so far. This study aimed at the completion of the structure and the sequence of the human ASL gene, the development of a genomic DNA-based system for mutation analysis and, finally, the characterisation of the molecular genetic background of ASL deficiency in 27 unrelated patients. This report provides transcript variants, the complete sequence of the human ASL gene and a complete ASL homologue on chromosome 22. The homologue was formerly thought to be a pseudogene but was found, in this study, to be correlated with an immunoglobulin-lambda-like mRNA. On the basis of the novel sequence data, a polymerase reaction chain system for mutation-screening in all 16 coding exons of the ASL gene was established and applied to the analysis of the ASL-deficient patients. We found mutations in all of the 54 investigated alleles and identified 23 (19 novel) different mutations. Some mutational hot-spots were identified (mainly in exons 4, 5, and 7) as were several predominant mutations: IVS5+1G-->A (15 alleles), c.532G-->A (7), c.346C-->T (6), c.1153C-->T (4). This study introduces a system for mutation analysis in the ASL gene, thereby elucidating the genetic background of ASL deficiency, which was found to be associated with considerable allelic heterogeneity.
