Methylenetetrahydrofolate reductase (MTHFR) catalyses the reduction of 5, 10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a methyl donor for the re-methylation of homocysteine to methionine. A thermolabile variant of this enzyme, present in approximately 35% of alleles in the North American population, has been associated with cardiovascular disease, neural tube defects, and colon cancer. A cDNA of 2.2kb for human MTHFR has been expressed and results in an active enzyme, but the cDNA and genomic sequences 5' to the ATG start site have not been adequately investigated. The characterization of the 5' region of the human MTHFR gene is reported here. Four additional 5' exonic sequences were localized to a 4kb genomic fragment. The original exon 1 extends directly upstream into a 5' UTR. Three other 5' exons (two with open reading frames) are alternatively spliced into a common splice acceptor site, generating cDNAs with 4 possible 5' ends. The N-terminal peptide sequence of the porcine MTHFR has not been identified in the human sequence suggesting that the missing human coding sequence might be localized further upstream or not conserved across species. A putative chloride ion channel gene (ClC-6) was located in the opposite orientation, at 3.5kb upstream of the original ATG codon, suggesting an overlap with the MTHFR gene and potential co-localization of regulatory elements. A CpG island was identified in the region of a 5' exon (43S) suggesting that a transcription start site and a promoter might be nearby. This work is relevant in understanding the regulation of this important enzyme in folate metabolism.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.21523 |
| Date | January 1999 |
| Creators | Chan, Manuel |
| 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: 001657831, proquestno: MQ50734, Theses scanned by UMI/ProQuest. |
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