MTHFR Gene Structure

Home Folate pathway Initial Discovery Clinical Aspects Gene Cloning Chromosome Locus Gene Structure Inheritance Mutation & Frequency Protein Properties Diagnosis&Treatment Works Cited MTHFR Links

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).