Genomic structure and transcript variants of the human methylenetetrahydrofolate reductase gene

The human 5,10-methylenetetrahydrofolate reductase (MTHFR) represents a maj or enzyme in the folate-dependent regulation of methionine and homocysteine concentrations. Different MTHFR mutations lead either to severe homocystin uria as a multisystem disorder or to moderate hyperhomocysteinaemia, which is a common risk factor for disorders ranging from cardiovasculopathy to sp ina bifida. The N-terminal part of the human MTHFR gene is incompletely cha racterised. We report the completed genomic structure of this gene includin g three novel exonic sequences on the basis of a 5'-RACE and a 4.2 kb clone d fragment of human genomic DNA. We demonstrate the existence of four MTHFR transcripts differing in their first exons. The diversity of transcripts i s due to alternative transcription initiation and alternative splicing. Thr ee 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, A P1, AP2, CAAT or CC boxes. Furthermore, we provide evidence that there are no TATA-box elements to regulate the human MTHFR gene. The results of our s tudy render the full-length characterisation of affected alleles in severe homocystinuria and moderate hyperhomocysteinaemia due to MTHFR deficiency a nd provide a basis for investigating the regulation of the human MTHFR gene .