Seven novel mutations in the methylenetetrahydrofolate reductase gene and genotype/phenotype correlations in severe methylenetetrahydrofolate reductase deficiency

Am J Hum Genet. 1995 May;56(5):1052-9.


5-Methyltetrahydrofolate, the major form of folate in plasma, is a carbon donor for the remethylation of homocysteine to methionine. This form of folate is generated from 5,10-methylenetetrahydrofolate through the action of 5,10-methylenetetrahydrofolate reductase (MTHFR), a cytosolic flavoprotein. Patients with an autosomal recessive severe deficiency 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 with severe MTHFR deficiency. We report here the characterization of seven novel mutations in this gene: six missense mutations and a 5' splice-site defect that activates a cryptic splice site in the coding sequence. 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 associated with extremely low activity (0%-3%) and onset of symptoms within the 1st year of age. Other missense mutations (arginine to cysteine and arginine to glutamine) are associated with higher enzyme activity and later onset of symptoms.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Age of Onset
  • Amino Acid Sequence
  • Base Sequence
  • Child, Preschool
  • Female
  • Genotype
  • Homozygote
  • Humans
  • Infant
  • Male
  • Metabolism, Inborn Errors / enzymology*
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • Molecular Sequence Data
  • Mutation / genetics*
  • Oxidoreductases Acting on CH-NH Group Donors / deficiency*
  • Oxidoreductases Acting on CH-NH Group Donors / genetics*
  • Phenotype
  • RNA Splicing
  • Sequence Homology, Amino Acid
  • Tetrahydrofolate Dehydrogenase / genetics
  • Tetrahydrofolates / metabolism*


  • Tetrahydrofolates
  • 5,10-methylenetetrahydrofolic acid
  • Oxidoreductases Acting on CH-NH Group Donors
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • Tetrahydrofolate Dehydrogenase