Genomic structure and transcript variants of the human methylenetetrahydrofolate reductase gene

The human 5,10-methylenetetrahydrofolate reductase (MTHFR) represents a major enzyme in the folate-dependent regulation of methionine and homocysteine concentrations. Different MTHFR

mutations lead either to severe homocystinuria as a multisystem disorder or to moderate hyperhomocysteinaemia, which is a common risk factor for disorders ranging from cardiovasculopathy to

spina bifida. The N-terminal part of the human MTHFR gene is incompletely characterised. We report the completed genomic structure of this gene including three novel exonic sequences on the

basis of a 5′-RACE and a 4.2 kb cloned fragment of human genomic DNA. We demonstrate the existence of four MTHFR transcripts differing in their first exons. The diversity of transcripts is

due to alternative transcription initiation and alternative splicing. Three putative polypeptides of 657, 698, and 680 amino acids are encoded. The novel genomic sequence described here

includes putative promoter regions as suggested by the presence of regions homologue to binding sites for SP1, AP1, AP2, CAAT or GC boxes. Furthermore, we provide evidence that there are no

TATA-box elements to regulate the human MTHFR gene. The results of our study render the full-length characterisation of affected alleles in severe homocystinuria and moderate

hyperhomocysteinaemia due to MTHFR deficiency and provide a basis for investigating the regulation of the human MTHFR gene.

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