A COMMON MUTATION IN THE METHYLENETETRAHYDROFOLATE REDUCTASE GENE IS ASSOCIATED WITH AN ACCUMULATION OF FORMYLATED TETRAHYDROFOLATES IN RED-BLOOD-CELLS

A common mutation (C677T) in the gene encoding for methylenetetrahydro folate reductase (MTHFR) (5-methyltetrahydrofolate: (acceptor) oxidore ductase, EC 1.7.99.5), a key regulatory enzyme in one-carbon metabolis m, results in a thermolabile variant of the MTHFR enzyme with reduced activity in vitro. In the present study we used a chromatographic meth od for folate analysis to test the hypothesis that this mutation would be associated with altered distribution of red blood cell (RBC) folat es. An alteration was found as manifested by the presence of formylate d tetrahydrofolate polyglutamates in addition to methylated derivative s in the RBCs from homozygous mutant individuals. 5-Methyltetrahydrofo late polyglutamates were the only folate form found in RBCs from indiv iduals with the wild-type genotype. Existence of formylated folates in RBCs only from individuals with the thermolabile MTHFR is consistent with the hypothesis that there is in vivo impairment in the activity o f the thermolabile variant of MTHFR and that this impairment results i n an altered distribution of RBC folates.