ABSTRACT
With the identification of hyperhomocysteinemia as a risk factor for cardiovascular
disease, an understanding of the genetic determinants of plasma homocysteine is important
for prevention and treatment. It has been known for some time that homocystinuria,
a rare inborn error of metabolism, can be due to genetic mutations that severely disrupt
homocysteine metabolism. A more recent development is the finding that milder, but
more common, genetic mutations in the same enzymes might also contribute to an elevation
in plasma homocysteine. The best example of this concept is a missense mutation (alanine
to valine) at base pair (bp) 677 of methylenetetrahydrofolate reductase (MTHFR), the
enzyme that provides the folate derivative for conversion of homocysteine to methionine.
This mutation results in mild hyperhomocysteinemia, primarily when folate levels are
low, providing a rationale (folate supplementation) for overcoming the genetic deficiency.
Additional genetic variants in MTHFR and in other enzymes of homocysteine metabolism
are being identified as the cDNAs/genes become isolated. These variants include a
glutamate to alanine mutation (bp 1298) in MTHFR, an aspartate to glycine mutation
(bp 2756) in methionine synthase, and an isoleucine to methionine mutation (bp 66)
in methionine synthase reductase. These variants have been identified relatively recently;
therefore additional investigations are required to determine their clinical significance
with respect to mild hyperhomocysteinemia and vascular disease.
KEYWORD
Homocysteine - folate - genetics - methylenetetrahydrofolate reductase - methionine
synthase
