title: 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.
authors: Dipartimento di Neurochirurgia, Istituto G. Gaslini, Genova, Italy.
authors: P
authors: P
authors: De Marco
authors: A
authors: A
authors: Moroni
authors: E
authors: E
authors: Merello
authors: R
authors: R
authors: de Franchis
authors: L
authors: L
authors: Andreussi
authors: R H
authors: RH
authors: Finnell
authors: R C
authors: RC
authors: Barber
authors: A
authors: A
authors: Cama
authors: V
authors: V
authors: Capra
mesh_terms: D020413:3' Untranslated Regions; D001483:Base Sequence; D015139:Blotting, Southern; D002352:Carrier Proteins / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid / Q000235:genetics* / Q000502:physiology; D017261:Glycosylphosphatidylinositols / Q000235:genetics; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D009436:Neural Tube Defects / Q000209:etiology* / Q000235:genetics; D016366:Open Reading Frames; D010375:Pedigree; D018807:Polymorphism, Single-Stranded Conformational; D011956:Receptors, Cell Surface; D012307:Risk Factors; D016415:Sequence Alignment
chemical_list: D020413:3' Untranslated Regions; D002352:Carrier Proteins; D058973:Folate Receptors, GPI-Anchored; D017261:Glycosylphosphatidylinositols; D011956:Receptors, Cell Surface; D005492:Folic Acid