Gene structure of human and mouse methylenetetrahydrofolate reductase (MTHFR) |
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Authors: | Philippe Goyette Aditya Pai Renate Milos Phyllis Frosst Pamela Tran Zhoutao Chen Manuel Chan Rima Rozen |
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Institution: | (1) Departments of Human Genetics, Pediatrics, and Biology, McGill University Health Center, Montreal, Quebec, Canada H3H 1P3, CA |
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Abstract: | Methylenetetrahydrofolate reductase (MTHFR) catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate,
a co-substrate for homocysteine remethylation to methionine. A human cDNA for MTHFR, 2.2 kb in length, has been expressed
and shown to result in a catalytically active enzyme of approximately 70 kDa. Fifteen mutations have been identified in the
MTHFR gene: 14 rare mutations associated with severe enzymatic deficiency and 1 common variant associated with a milder deficiency.
The common polymorphism has been implicated in three multifactorial diseases: occlusive vascular disease, neural tube defects,
and colon cancer. The human gene has been mapped to chromosomal region 1p36.3 while the mouse gene has been localized to distal
Chromosome (Chr) 4. Here we report the isolation and characterization of the human and mouse genes for MTHFR. A human genomic
clone (17 kb) was found to contain the entire cDNA sequence of 2.2 kb; there were 11 exons ranging in size from 102 bp to
432 bp. Intron sizes ranged from 250 bp to 1.5 kb with one exception of 4.2 kb. The mouse genomic clones (19 kb) start 7 kb
5′ exon 1 and extend to the end of the coding sequence. The mouse amino acid sequence is approximately 90% identical to the
corresponding human sequence. The exon sizes, locations of intronic boundaries, and intron sizes are also quite similar between
the two species. The availability of human genomic clones has been useful in designing primers for exon amplification and
mutation detection. The mouse genomic clones will be helpful in designing constructs for gene targeting and generation of
mouse models for MTHFR deficiency.
Received: 28 January 1998 / Accepted: 9 April 1998 |
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