Summary
Moderate hyperhomocysteinemia in pregnant women has been associated with an increased
risk of neural tube defects (NTDs). Periconceptional supplementation with multi-vitamins
containing folic acid may normalize homocysteine metabolism and decrease the NTD risk.
The C677 T variant of the MTHFR gene coding for a thermolabile enzyme has been described
as the first genetic risk factor that accounts for a group of NTDs characterized by
low maternal folate status and high homocysteine concentrations. Another common mutation
of the same MTHFR gene, A1298 C, has also been described as an NTD risk factor. In
addition to abnormal folate metabolism, anything that compromises the internalization
of folate into the cell may be involved in the pathogenesis of NTDs. For this reason,
a common polymorphism in the RFC-1 gene encoding the reduced folate carrier protein
(A80 G) could also be an additional NTD risk factor. In the present study we examined
the genotypic distributions and the allele frequencies of MTHFR A1298 C and RFC-1
A80 G polymorphisms in DNA samples from healthy Italian individuals and compared them
to the frequencies observed in NTD cases and their parents. By means of restriction
enzymatic analysis, we determined that the frequency of the mutated C allele of the
A1298 C mutation was 0.25 among control individuals, which is in the range of that
recently reported in other ethnic groups. However, we report that the mutant C allele
frequencies are significantly higher among NTD cases and case mothers than among controls
(0.39, 0.44, 0.25). Furthermore, for the RFC-1 A80 G mutation, we found that the frequency
of the G allele of the RFC-1 mutation was 0.46 in the control population, suggesting
that this is a common polymorphism in the Italian population. In spite of the high
prevalence of the 80 G/G genotype among healthy subjects, we observed an increased
frequency of the G allele in NTD-affected children, and their mothers and fathers.
These preliminary results indicate that both the MTHFR and RFC-1 polymorphisms may
play a role in NTD risk, at least in the Italian population. Further studies should
be directed toward the evaluation of the level of risk conferred by the mutant MTHFR
and RFC-1 genotypes, as well as the interaction between these genetic determinants
and other nutritional and environmental factors.
Key words
NTDs - Folate metabolism and transport - MTHFR gene - RFC-1 gene - SNPs
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Dr. Valeria Capra
Istituto G. Gaslini
Largo G. Gaslini, 5
16147 Genova
Italia
Email: capraval@tin.it
Email: valeriacapra@ospedale-gaslini.ge.it
