Folate pathway gene alterations in patients with neural tube defects

Abstract

Periconceptional folate supplementation reduces the recurrence and occurrence risk of neural tube defects (NTD) by as much as 70%, yet the protective mechanism remains unknown. Inborn errors of folate and homocysteine metabolism may be involved in the aetiology of NTDs. Previous studies have demonstrated that both homozygosity for the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene, and combined heterozygosity for the C677T and for another mutation in the same gene, the A1298C polymorphism, represent genetic risk factors for NTDs. In an attempt to identify additional folate related genes that contribute to NTD pathogenesis, we performed molecular genetic analysis of folate receptors (FRs). We identified 4 unrelated patients out of 50 with de novo insertions of pseudogene (PS)-specific mutations in exon 7 and 3'UTR of the FRalpha gene, arising by microconversion events. All of the substitutions affect the carboxy-terminal amino acid membrane tail, or the GPI anchor region of the nascent protein. Furthermore, among 150 control individuals, we also identified one infant with a gene conversion event within the FRalpha coding region. This study, though preliminary, provides the first genetic association between molecular variations of the FRalpha gene and NTDs and suggests that this gene can act as a risk factor for human NTD.

Suppression of Uracil-DNA Glycosylase Induces Neuronal Apoptosis

“…Since the expression of UNG is under cell cycle control and is associated with the DNA replication machinery (52,54), the suppression of this machinery may down-regulate UNG expression. Perturbed one-carbon metabolism has been suggested to play a role in the etiology of neural tube defects and anemia, both associated with diminished cell division (37,55). In addition, CBS knockout mice have highly reduced body weights as compared with wild-type mice, a factor that may be linked to decreased proliferating rate in the tissues of these animals.…”

The Rate and Tract Length of Gene Conversion between Duplicated Genes

“…There are a number of human diseases caused by gene conversion, as reviewed by Chen et al [41] in this issue (see also [3]). In many cases, diseases are caused by gene conversion that transfer a mutation from a pseudogenized duplicate to the functional copy, resulting in missense mutation [82–84], nonsense mutation [85], frameshift [86,87], change of splicing site [88]. These conversions occur between highly similar sequences (more than 90%, see [3]), which seems to be slightly higher than that for yeast and rodent.…”

Genetic and Epigenetic Contributions to Human Nutrition and Health: Managing Genome–Diet Interactions

“…Folate supplementation can reduce the risk of these disorders developing, with genetically susceptible individuals/populations accruing the most benefit; this suggests that folate nutrition can compensate for genetically induced impairments in folate metabolism (26). However, the biochemical mechanisms underlying folate-related pathologies have remained elusive despite intensive investigation.…”