7 NOVEL MUTATIONS IN THE METHYLENETETRAHYDROFOLATE REDUCTASE GENE ANDGENOTYPE-PHENOTYPE CORRELATIONS IN SEVERE METHYLENETETRAHYDROFOLATE REDUCTASE DEFICIENCY

5-Methyltetrahydrofolate, the major form of folate in plasma, is a car bon donor for the remethylation of homocysteine to methionine. This fo rm of folate is generated from 5,10-methylenetetrahydrofolate through the action of 5,10-methylenetetrahydrofolate reductase (MTHFR), a cyto solic flavoprotein. Patients with an autosomal recessive severe defici ency of MTHFR have homocystinuria and a wide range of neurological and vascular disturbances. We have recently described the isolation of a cDNA for MTHFR and the identification of two mutations in patients wit h severe MTHFR deficiency. We report here the characterization of seve n novel mutations in this gene: six missense mutations and a 5' splice -site defect that activates a cryptic splice site in the coding sequen ce. We also present a preliminary analysis of the relationship between genotype and phenotype for all nine mutations identified thus far in this gene. A nonsense mutation and two missense mutations (proline to leucine and threonine to methionine) in the homozygous state are assoc iated with extremely low activity (0%-3%) and onset of symptoms within the Ist year of age. Other missense mutations (arginine to cysteine a nd arginine to glutamine) are associated with higher enzyme activity a nd later onset of symptoms.