Genetic Models Associated With Folate Metabolism

There are now more than 60 mouse genetic models in which NTD have been described as part of the mutant phenotype (10,11). The models can be categorized into (1) those characterized by the persistent presence of an open neural tube (i.e., comparable to the human NTD anencephaly and meningomyelocele) and (2) those in which the neural tube closes but develops abnormally in various ways. The relevance of this second group of defects to human NTD is unclear and, here, we concentrate on the first group as examples of defective neural tube closure. In particular, we focus on those models in which gene mutations cause defects where folate metabolism is implicated either in the pathogenetic mechanism or in providing protection against development of the NTD (Table 1).

In addition to mouse strains, for which the nature of the mutant gene is known, there are a number of naturally occurring strains in which the mutant gene has not yet been identified. Characterization of these genes should give further information about the pathways with which folic acid interacts and will provide further candidate genes to be analyzed in human NTD cases.

Axial Defects

In the axial defects (Axd) mutant mouse, open spinal NTD and tail flexion defects are observed in presumed homozygous mice among the offspring of heterozygote crosses (12). The mutation does not affect mean litter size or resorption rate, suggesting that Axd does not cause lethality. Tail defects are also observed in some heterozygotes and seem likely to result from delayed closure of the low spinal neural tube (12). As in several other mouse models, genetic background has a significant effect on the penetrance of the defect, with approximately half of the heterozygotes displaying a tail phenotype on the most susceptible background (12,13).

In terms of folate-preventable NTD, the Axd mouse does not provide an ideal model, as there is no effect of maternal supplementation with folinic acid or vitamin B12 (14). In contrast, maternal methionine supplementation is reported to reduce the incidence of caudal NTD among the offspring of heterozygous crosses by approx 40% (13,14). This may indicate an abnormality in a folate-related pathway because 5-methyl tetrahydrofolate is the one-carbon donor for conversion of homocysteine to methionine by methionine synthase (Fig. 1, reaction 1). However, a simple methionine

Table 1

Summary of Genetic Mouse Models for Folate-Related NTD and Associated Defects

Table 1

Summary of Genetic Mouse Models for Folate-Related NTD and Associated Defects

Mutant

Origin

NTD?

Gene

Folate-responsive?

Axial defects

Natural

Yes

NDa

No (methionine

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