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

Abstract

Elevated homocysteine (Hcy) levels are observed in two apparently unrelated diseases: neural-tube defects (NTD) and premature vascular disease. Defective human methionine synthase (MS) could result in elevated Hcy levels. We sequenced the coding region of MS in 8 hyperhomocysteinaemic patients (4 NTD patients and 4 patients with pregnancies complicated by spiral arterial disease, SAD). We identified only one mutation resulting in an amino acid substitution: an A-->G transition at bp 2756, converting an aspartic acid (D919) into a glycine (G). We screened genomic DNA for the presence of this mutation in 56 NTD patients, 69 mothers of children with NTD, 108 SAD patients and 364 controls. There was no increased prevalence of 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 vascular disease. We then examined the mean Hcy levels for each MS genotype. There was no correlation between GG- or AG-genotype and Hcy levels. The D919G mutation is thus a fairly prevalent, and probably benign polymorphism. This study, though limited, provides no evidence for a major involvement of MS in the aetiology of homocysteine-related diseases such as NTD or vascular disease.

Study of MTHFR and MS polymorphisms as risk factors for NTD in the Italian population

“…The A1298C frequencies were 0.39, 0.44, and 0.36 among patients, mothers, and fathers, respectively. The frequency of the G allele of the MS A2756G polymorphism was 0.15 in the control population, which was in agreement with the incidence reported by other investigators (van der Put et al 1997b). No increased prevalence of this mutated allele was found in NTD families, although a slightly higher frequency was present in patients and mothers (0.11) and in fathers (0.13).…”

“…An A-to-G transition at bp 2756, which converts an aspartic acid to glycine, has been investigated in NTD patients. No increased prevalence of the 2756GG and 2756AG genotypes was found in patients, and no correlation was observed between these two genotypes and homocysteine levels (Morrison et al 1997;van der Put et al 1997b;Shaw et al 1999). Additional studies on MS variants are required to address the role of this variant on NTD risk.…”

“…To screen for the MS mutation (A2756G), an appropriate region of genomic DNA was amplified by using two specific primers (5Ј-GGTGTGTTCCCAGCTGTTA GATG-3Ј and 5Ј-GACACTGAAGACCTCTGATTTGA AC-3Ј) and digested with HaeIII (van der Put et al 1997b). A 2756AA genotype results in an uncut fragment of 265 bp, whereas a 2756AG genotype gives three fragments of 265, 180, and 85 bp.…”

5-Methyltetrahydrofolate-homocysteine methyltransferase gene polymorphism (MTR) and risk of head and neck cancer

“…An adenine to guanine transition at position 2756 (rs185087) of the MTR gene results in the substitution of the amino acid, aspartic acid, with glycine in codon 919 of the protein and is related to alterations in the folate metabolic pathway, thus possibly influencing the risk of cancer (12,13).…”

Study the Correlation Between Polymorphism of MTHFR Thrombophilic Genes and Pregnancy Loss in Ahvaz City

“…Reduction of MTHFR enzyme activity lowers the substrate for methionine synthetase. Consequently, production of methionine stops and we will have a rise in the level of homocysteine 13 . Polymorphisms (such as A1298C and C677T) of individual nucleotides in MTHFR encoding gene is considered to be one of the major factors which cause thrombophilia 12 .…”