Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme in folate metabolism. Severe enzymatic deficiency results in metabolic disease with occasional early demise. Mild deficiency is due to a common polymorphism (A222V) which increases risk for several common disorders. Pharmacogenetic studies of the antifolate methotrexate on Mthfr heterozygous knockout mice (Mthfr +/-), a model of the mild human deficiency, revealed significantly higher apoptosis rates in several tissues compared to wildtype mice (Mthfr +/+). These results suggest that mild MTHFR deficiency is a risk factor for methotrexate toxicity in mice and possibly in humans. A new medication, metafolin, was administered to Mthfr +/- mothers to assess survival of their Mthfr -/- pups. Survival rate of pups at 5 weeks of age from treated mothers was significantly higher than that from untreated mothers (54% versus 20%). The results of this study suggest that metafolin could be useful for treatment of severe MTHFR deficiency in humans.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.80299 |
| Date | January 2004 |
| Creators | Karp, Natalya |
| 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 Human Genetics.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 002141233, proquestno: AAIMQ98668, Theses scanned by UMI/ProQuest. |
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