Sequence analysis of the coding region of human methionine synthase: relevance to hyperhomocysteinaemia in neural-tube defects and vascular disease

Elevated homocysteine (Hcy) levels are observed in two apparently unrelateddiseases: neural-tube defects (NTD) and premature vascular disease.Defective human methionine synthase (MS) could result in elevated Hcylevels. We sequenced the coding region of MS in 8 hyperhomocysteinaemicpatients (4 NTD patients and 4 patients with pregnancies complicated byspiral arterial disease, SAD). We identified only one mutation resulting inan amino acid substitution: an A-->G transition at bp 2756, convertingan aspartic acid (D919) into a glycine (G). We screened genomic DNA for thepresence of this mutation in 56 NTD patients, 69 mothers of children withNTD, 108 SAD patients and 364 controls. There was no increased prevalenceof the GG and AG genotypes in NTD patients, their mothers or SAD patients.The D919G mutation does not seem to be a risk factor for NTD or vasculardisease. We then examined the mean Hcy levels for each MS genotype. Therewas no correlation between GG- or AG-genotype and Hcy levels. The D919Gmutation is thus a fairly prevalent, and probably benign polymorphism. Thisstudy, though limited, provides no evidence for a major involvement of MSin the aetiology of homocysteine-related diseases such as NTD or vasculardisease.