Characterization of mutations in severe methylenetetrahydrofolate reductase deficiency reveals an FAD-responsive mutation

Sahar Sibani, Daniel Leclerc, Ilan S. Weisberg, Erin O'Ferrall, David Watkins, Carmen Artigas, David S. Rosenblatt, Rima Rozen

Research output: Contribution to journalArticlepeer-review

50 Scopus citations

Abstract

Methylenetetrahydrofolate reductase (MTHFR) synthesizes 5-methyltetrahydrofolate, a major methyl donor for homocysteine remethylation to methionine. Severe MTHFR deficiency results in marked hyperhomocysteinemia and homocystinuria. Patients display developmental delay and a variety of neurological and vascular symptoms. Cloning of the human cDNA and gene has enabled the identification of 29 rare mutations in homocystinuric patients and two common variants [677C>T (A222V) and 1298A>C (E429A)] with mild enzymatic deficiency. Homozygosity for 677C>T or combined heterozygosity for both polymorphisms is associated with mild hyperhomocysteinemia. In this communication, we describe four novel mutations in patients with homocystinuria: two missense mutations (471C>G, I153M; 1025T>C, M338T), a nonsense mutation (1274G>A, W421X), and a 2-bp deletion (1553delAG). We expressed the 1025T>C mutation as well as two previously reported amino acid substitutions [983A>G (N324S) and 1027T>G (W339G)] and observed decreased enzyme activity at 10%, 36%, and 21% of control levels, respectively, with little or no effect on affinity for 5-methyltetrahydrofolate. One of these mutations, 983A>G (N324S), showed flavin adenine dinucleotide (FAD) responsiveness in vitro. Expression of these mutations in cis with the 677C>T polymorphism, as observed in the patients, resulted in an additional 50% decrease in enzyme activity. This report brings the total to 33 severe mutations identified in patients with severe MTHFR deficiency.

Original languageEnglish
Pages (from-to)509-520
Number of pages12
JournalHuman Mutation
Volume21
Issue number5
DOIs
StatePublished - 2003
Externally publishedYes

Keywords

  • Folate
  • Homocysteine
  • Homocystinuria
  • MTHFR
  • Methylenetetrahydrofolate reductase
  • Mutations

Fingerprint

Dive into the research topics of 'Characterization of mutations in severe methylenetetrahydrofolate reductase deficiency reveals an FAD-responsive mutation'. Together they form a unique fingerprint.

Cite this