Methylenetetrahydrofolate reductase catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a carbon donor for the remethylation of homocysteine to methionine. Patients with severe MTHFR deficiency have $<$20% residual enzyme activity, moderate hyperhomocysteinemia, vascular lesions and neurological dysfunction. Mildly-deficient individuals with a thermolabile enzyme are at increased risk for developing cardiovascular disease. / Two MTHFR sequence changes were identified. The first was a C to T transition at bp 764 altering a proline to a leucine codon; this change was found in one severely-deficient patient. The second was a C to T transition at bp 677, substituting a valine for a highly-conserved alanine codon. The $ rm A to V$ substitution was identified on 35-40% of chromosomes. Expression of the $ rm A to V$ mutation in prokaryotic cells revealed increased thermolability over the wild-type enzyme. Genotyping for the $ rm A to V$ mutation in three vascular disease studies showed that it was associated with mild hyperhomocysteinemia, a risk factor for vascular disease. / The preventative effects of folate supplementation on the occurrence and recurrence of neural tube defects (NTDs) have been repeatedly demonstrated. The curly-tail (ct) mouse model for NTDs was used to investigate the involvement of MTHFR in these defects. Ct mice had significantly increased homocysteine levels although differences in MTHFR activity were not demonstrated. The mouse MTHFR gene was mapped to distal chromosome 4, close to the major gene for NTDs in ct. MTHFR is suggested as a candidate locus for the ct defect.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.23399 |
| Date | January 1995 |
| Creators | Frosst, Phyllis D. |
| Contributors | Rozen, Rima (advisor) |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Master of Science (Department of Biology.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001485771, proquestno: MM12196, Theses scanned by UMI/ProQuest. |
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