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

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Summary

Introduction

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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