Correction of disease-causing CBS mutations in yeast.
Nat Genet
; 19(1): 91-3, 1998 May.
Article
em En
| MEDLINE
| ID: mdl-9590298
ABSTRACT
Mutations in cystathionine beta-synthase (CBS) are known to cause homocystinuria, a recessive disorder characterized by excessive levels of total homocysteine (tHcy) in plasma. The primary cause of mortality is thromboembolism induced by the excessive tHcy levels. Mild increases in tHcy levels are a significant risk factor in the development of vascular disease in the general population. This can result from heterozygosity at the CBS locus or polymorphic variation in other enzymes involved in homocysteine re-methylation. We report here that a mutation which deletes the carboxy-terminal 145 amino acids of CBS can functionally suppress the phenotype of several CBS mutant alleles found in homocystinurics when expressed in yeast. This C-terminal domain of CBS acts to inhibit enzymatic activity and is in turn regulated by S-adenosylmethionine (AdoMet), a positive effector of CBS. Our results indicate that most mutations found in homocystinurics do not cause dysfunction of the catalytic domain, but rather interfere with the activation of the enzyme. These findings suggest a new drug target to treat homocystinuria and homocysteine-related vascular disease.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Saccharomyces cerevisiae
/
Terapia Genética
/
Cistationina beta-Sintase
/
Homocistinúria
/
Mutação
Tipo de estudo:
Risk_factors_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
1998
Tipo de documento:
Article