Folate pathway gene alterations in patients with neural tube defects

Periconceptional folate supplementation reduces the recurrence and occurren ce risk of neural tube defects (NTD) by as much as 70%, yet the protective mechanism remains unknown. Inborn errors of folate and homocysteine metabol ism may be involved in the aetiology of NTDs. Previous studies have demonst rated that both homozygosity for the C677T mutation in the methylenetetrahy drofolate reductase (MTHFR) gene, and combined heterozygosity for the C677T and for another mutation in the same gene, the A1298C polymorphism, repres ent genetic risk factors for NTDs, In an attempt to identify additional fol ate related genes that contribute to NTD pathogenesis, we performed molecul ar genetic analysis of folate receptors (FRs), We identified 4 unrelated pa tients out of 50 with de novo insertions of pseudogene (PS)-specific mutati ons in exon 7 and 3'UTR of the FR alpha gene, arising by microconversion ev ents. All of the substitutions affect the carboxy-terminal amino acid membr ane tail, or the GPI anchor region of the nascent protein. Furthermore, amo ng 150 control individuals, we also identified one infant with a gene conve rsion event within the FR alpha coding region. This study, though prelimina ry, provides the first genetic association between molecular variations of the FR alpha gene and NTDs and suggests that this gene can act as a risk fa ctor for human NTD, Am, J, Med, Genet. 95: 216-223, 2000, (C) 2000 Wiley-Li ss, Inc.