title: Severe and mild mutations in cis for the methylenetetrahydrofolate reductase (MTHFR) gene, and description of five novel mutations in MTHFR.
abstract: Methylenetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolate, a methyl donor in the conversion of homocysteine to methionine. Patients with severe MTHFR deficiency have hyperhomocysteinemia, hypomethioninemia, and a range of neurological and vascular findings with a variable age at onset. We have previously described nine mutations in patients with severe MTHFR deficiency. A mild form of MTHFR deficiency, associated with a thermolabile enzyme, has been proposed as a genetic risk factor for cardiovascular disease and for neural tube defects. We have shown that a common missense mutation (an alanine-to-valine substitution) encodes this thermolabile variant. We now report an additional five mutations causing severe MTHFR deficiency and an analysis of genotype (alanine/valine status) and enzyme thermolability in 22 patients with this inborn error of metabolism. Six of these patients have four mutations in the MTHFR gene-two rare mutations causing severe deficiency and two mutations for the common alanine-to-valine mutation that results in thermolability. Even in severe MTHFR deficiency, the thermolabile variant is frequently observed, and there is a strong relationship between the presence of this variant and increased enzyme thermolability.
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
authors.forename: P
authors.initials: P
authors.lastname: Goyette
authors.forename: B
authors.initials: B
authors.lastname: Christensen
authors.forename: D S
authors.initials: DS
authors.lastname: Rosenblatt
authors.forename: R
authors.initials: R
authors.lastname: Rozen
mesh_terms: D000293:Adolescent; D000409:Alanine; D004252:DNA Mutational Analysis; D005260:Female; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000172:deficiency* / Q000235:genetics*; D017354:Point Mutation / Q000235:genetics*; D014633:Valine
chemical_list: D000587:Oxidoreductases Acting on CH-NH Group Donors; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D014633:Valine; D000409:Alanine