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Folate pathway gene alterations in patients with neural tube defects
P De Marco1, A Moroni, E Merello
1Dipartimento di Neurochirurgia, Istituto G. Gaslini, Genova, Italy.
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.
Insights
Folate supplementation prevents neural tube defects (NTDs), but mechanisms are unclear. This study links mutations in the folate receptor alpha (FRalpha) gene to NTD risk, suggesting FRalpha as a potential genetic factor.
Area of Science:
- Genetics
- Developmental Biology
- Nutritional Science
Background:
- Periconceptional folate supplementation significantly reduces neural tube defect (NTD) risk, but the underlying protective mechanisms are not fully understood.
- Genetic factors, including mutations in methylenetetrahydrofolate reductase (MTHFR), are known risk factors for NTDs.
- Investigating other folate-related genes is crucial for a comprehensive understanding of NTD etiology.
Purpose of the Study:
- To identify novel folate-related genes contributing to the pathogenesis of neural tube defects (NTDs).
- To investigate the role of folate receptors (FRs), specifically the FRalpha gene, in NTD development.
Main Methods:
- Molecular genetic analysis of folate receptors (FRs) in patients with NTDs.
- Identification and characterization of mutations within the FRalpha gene, including de novo insertions and gene conversion events.
- Analysis of mutations in exon 7 and the 3' untranslated region (3'UTR) of the FRalpha gene.
Main Results:
- Four out of 50 unrelated patients with NTDs exhibited de novo insertions of pseudogene (PS)-specific mutations in the FRalpha gene.
- These mutations occurred via microconversion events and affected critical regions of the FRalpha protein, including the membrane tail or GPI anchor region.
- One infant among 150 control individuals showed a gene conversion event within the FRalpha coding region.
Conclusions:
- This preliminary study provides the first genetic association between molecular variations in the FRalpha gene and neural tube defects (NTDs).
- The FRalpha gene is suggested to be a potential risk factor for human NTDs.
- Further research is warranted to elucidate the precise role of FRalpha gene variations in NTD pathogenesis.