Abstract
BackgroundCystathionine β-synthase (CBS) mediates conversion of homocysteine to cystathionine and deficiency in enzyme activity may lead to hyperhomocysteinemia/homocystinuria, which are often associated with mental retardation (MR). A large number of polymorphisms have been reported in the CBS gene, some of which impair its activity and among these, a T833C polymorphism in cis with a 68 bp insertion at 844 in the exon 8 is found to be associated with mild hyperhomocysteinemia in different ethnic groups.MethodsThe present study is aimed at investigating the association between T833C/844ins68 polymorphism and MR. One hundred and ninety MR cases were recruited after psychometric evaluation. Hundred and thirty-eight control subjects, two hundred and sixty-seven parents of MR probands and thirty cardiovascular disorder (CVD) patients were included for comparison. Peripheral blood was collected after obtaining informed written consent. The T833C/844ins68 polymorphism was investigated by PCR amplification of genomic DNA and restriction fragment length polymorphism analysis, followed by statistical analysis.ResultsThe genotypic distribution of the polymorphism was within the Hardy-Weinberg equilibrium. A slightly increased genotypic frequency was observed in the Indian control population as compared to other Asian populations. Both haplotype-based haplotype relative risk analysis and transmission disequilibrium test reveled lack of association of the T833C/844ins68 polymorphism with MR; nevertheless, the relative risk calculated was higher (>1) and in a limited number of informative MR families, preferential transmission of the double mutant from heterozygous mothers to the MR probands was noticed (χ2 = 4.00, P < 0.05).ConclusionThis is the first molecular genetic study of CBS gene dealing with T833C/844ins68 double mutation in MR subjects. Our preliminary data indicate lack of association between T833C/844ins68 polymorphism with MR. However, higher relative risk and biased transmission of the double mutation from heterozygous mothers to MR probands are indicative of a risk of association between this polymorphism with mental retardation.
Highlights
Cystathionine β-synthase (CBS) mediates conversion of homocysteine to cystathionine and deficiency in enzyme activity may lead to hyperhomocysteinemia/homocystinuria, which are often associated with mental retardation (MR)
Cystathionine β-synthase (CBS) catalyzes the condensation of serine and homocysteine to form cystathionine and abnormality in CBS activity is manifested in two major clinical conditions, viz. hyperhomocysteinemia and homocystinuria
We have investigated the occurrence of this double mutant in MR individuals
Summary
Cystathionine β-synthase (CBS) mediates conversion of homocysteine to cystathionine and deficiency in enzyme activity may lead to hyperhomocysteinemia/homocystinuria, which are often associated with mental retardation (MR). Since homocysteine is vasculotoxic as well as neurotoxic, hyperhomocysteinemia predisposes to cardiovascular disorder (CVD) and cognitive dysfunction [3,4]. Gross deficiency in CBS activity is associated with homocystinuria, an inborn recessive metabolic disorder [4]. The major pathologic abnormalities associated with homocystinuria include thromboembolism, ectopia lentis, osteoporosis, mental retardation (MR) and other neurological and psychiatric abnormalities [4]. MR associated with B12 and folate deficiency could be attributed to the neurotoxic effects of homocysteine since B12 and folate act as co-factors in the homocysteine to methionine remethylation pathway
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