Methylenetetrahydrofolate reductase (MTHFR) is a key regulatory enzyme in folate 
and homocysteine metabolism. Research performed during the past decade has 
clarified our understanding of MTHFR deficiencies that cause homocystinuria or 
mild hyperhomocysteinemia. Our cloning of the MTHFR coding sequence was 
initially followed by the identification of the first deleterious mutations in 
MTHFR, in patients with homocystinuria and marked hyperhomocysteinemia. Shortly 
thereafter, we identified the 677C-->T variant and showed that it encoded a 
thermolabile enzyme with reduced activity. Currently, a total of 41 rare but 
deleterious mutations in MTHFR, as well as about 60 polymorphisms have been 
reported. The 677C-->T (Ala222Val) variant has been particularly noteworthy 
since it has become recognized as the most common genetic cause of 
hyperhomocysteinemia. The disruption of homocysteine metabolism by this 
polymorphism influences risk for several complex disorders, including 
cardiovascular disease, neural tube defects and some cancers. We describe here 
the complex structure of the MTHFR gene, summarize the current state of 
knowledge on rare and common mutations in MTHFR and discuss some relevant 
findings in a mouse model for MTHFR deficiency.