It is now well recognized that periconceptional
folic acid or
folic acid containing multivitamin supplementation reduces the risk of
neural tube defects (NTDs). Recently we were able to show that homozygosity for a thermolabile variant of the
enzyme methylenetetrahydrofolate reductase is associated with an increased risk for
spina bifida in patients recruited from the Dutch population. However, this genetic risk factor could not account for all
folic acid preventable NTDs. In an attempt to identify additional
folate related
enzymes that contribute to NTD etiology we now studied the
methylenetetrahydrofolate dehydrogenase gene on chromosome 14q24 which encodes a single
protein with three catalytic properties important in the
folate metabolism. The
cDNA sequence of 38 familial and 79 sporadic patients was screened for the presence of mutations by single strand conformation polymorphism (SSCP) analysis followed by sequencing. Two amino acid substitutions were identified. The first one (R293H) was detected in a patient with familial
spina bifida and not in 300 control individuals. The mutation was inherited from the unaffected maternal grandmother and was also present in two younger brothers of the index patient, one of them displaying
spina bifida occulta and the other being unaffected. The second change turned out to be an
amino acid polymorphism (R653Q) that was present in both patients and controls with similar frequencies. Our results so far provide no evidence for a major role of the
methylenetetrahydrofolate-dehydrogenase (MTHFD) gene in NTD etiology. However, the identification of a mutation in one family suggests that this gene can act as a risk factor for human NTD.