1p36.22

Homocystinuria due to deficiency of methylenetetrahydrofolate reductase activity

This form of homocystinuria is caused by mutation in the 5,10-alpha-methylenetetrahydrofolate reductase gene. This homocystinuria is autosomal recessive and shows a wide range of clinical symptoms, such as developmental delay, severe mental retardation, perinatal death, psychiatric disturbances, and later-onset neurodegenerative disorders. In the classic form, both thermostable and thermolabile enzyme variants have been identified.

Cancer

In some cancers, folate and other nutrients involved in the MTHFR metabolic pathway appear to interact with MTHFR polymorphisms to further modify cancer risk. In most studies, MTHFR 677TT and 1298CC are associated with moderately reduced colorectal cancer risk, in particular in individuals who had higher folate levels. In individuals with low folate intake and/or high alcohol consumption, cancer risk may be increased. Morever, both adults and children with the variant forms of MTHFR seems to have a decreased risk of lymphoid leukemias. MTHFR polymorphisms were also associated with other cancers as breast, head and neck, liver, gastric or lung cancers.

Reduction of 5,10-methylenetetrahydrofolate (methyleneTHF), a donor for methylating dUMP to dTMP in DNA synthesis, to 5-methyltetrahydrofolate (methylTHF), the primary methyl donor for methionine synthesis, is catalyzed by MTHFR. Diminution in the activity of the MTHFR enzyme increases the pool of methyleneTHF at the expense of the pool of methylTHF. Enhanced availability of methyleneTHF in the DNA synthesis pathway reduces misincorporation of uracil into DNA, which might otherwise result in double-strand breaks during uracil excision repair processes, thus increasing the risk of chromosomal aberrations. Morever, the MTHFR polymorphisms influences DNA methylation status through interaction with folate status.

Coronary Artery Disease

The 677TT MTHFR allele was correlated with coronary artery disease. However, the role of this polymorphism in the causation of coronary artery disease is controversial.

Depression

Hyperhomocysteinemia and the 677TT genotype were significantly related to depression.