MTHFR Gene Structure
The MTHFR gene is over 20kb in size. It consists of 13 exons, each of which are 102-432bp in size (Goyette et al, 1998; Homberger et al, 2000). As will be discussed later in this page, for the first three possible exons, each transcript has only one (Homberger et al, 2000). The gene structure of the 11 exons discovered by Goyette et al (1998) is shown here.
Consideration of the human MTHFR gene’s regulatory region
reveals some interesting characteristics.
The regulatory region of the MTHFR gene contains consensus
promoter regions for CAAT and GC boxes, as well as for several other
known promoter elements (SP1, AP1, AP2).
Despite the presence of these regulatory regions, however, the
gene lacks the most common regulatory region—the
consensus TATA-box element seen in the majority of eukaryotic genes (Homberger
et al, 2000). While this is surprising, work on other genes involved in
homocysteine metabolism show a similar pattern (Chen et
al, 1997; Kraus
et al, 1998).
Analysis of the complete genomic structure suggests that both alternative initiation and alternative splicing occur in the gene (Homberger et al, 2000). Such a discovery gives an explanation for previously reported Western blot results, which indicated that human MTHFR can be found in two forms--a 77kDa polypeptide in most tissues and a 70kDa polypeptide in the liver (Frosst et al, 1995). Homberger and colleagues report the existence of four variants of the MTHFR polypeptide: MTHFR1 (two forms), MTHFR2, and MTHFR3. All variants are identical at the 3’ end, but are different at the 5’ end, indicating the occurrence of alternative initiation (See Figure) The two forms of MTHFR 1 appear to result from alternative splicing, with the difference being the presence or absence of three nucleotides (Hombeger et al, 2000).