Folate pathway gene alterations in patients with neural tube defects

Patrizia De Marco, Anna Moroni, Elisa Merello, Raffaella De Franchis, Luciano Andreussi, Richard H. Finnell, Robert Clinton Barber, Armando Cama, Valeria Capra

Research output: Contribution to journalArticlepeer-review

52 Scopus citations


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 methylenetetra-hydrofolate 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 FRα 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 FRα coding region. This study, though preliminary, provides the first genetic association between molecular variations of the FRα gene and NTDs and suggests that this gene can act as a risk factor for human NTD. (C) 2000 Wiley-Liss, Inc.

Original languageEnglish
Pages (from-to)216-223
Number of pages8
JournalAmerican Journal of Medical Genetics
Issue number3
StatePublished - 27 Nov 2000


  • Folate receptors
  • Folic acid
  • Neural tube defects


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