Association of combined GIF290T>C heterozygous mutation/FUT2 secretor variant with neural tube defects

Abstract

Funding informationRegion of Lorraine (France); Ministry of Health (PHRC COMET) Folate and vitamin B12 are needed for the proper embryo-fetal development possibly through their interacting role in the 1-carbon metabolism. Folate fortification reduces the prevalence of complex birth defects, and more specifically neural tube defects (NTDs). GIF and FUT2 are 2 genes associated with the uptake and blood level of vitamin B12. We evaluated GIF and FUT2 as predictors of severe birth defects, in 183 aborted fetuses compared with 375 healthy newborns. The GIF290C allele frequency was estimated to 0.4% in healthy newborns and to 8.1% in NTD fetuses (odds ratio 17.8 [95% confidence interval CI: 4.0-77.6]). The frequency of FUT2 rs601338 secretor variant was not different among groups. The GIF 290C heterozygous/ FUT2 rs601338 secretor variant combined genotype was reported in 6 of the 37 NTD fetuses, but not in other fetuses and healthy newborns (P < .0001). This GIF/FUT2 combined genotype has been previously reported in children with congenital gastric intrinsic factor (GIF) deficiency, with respective consequences on B12 binding activity and GIF secretion. In conclusion, a genotype reported in congenital GIF deficiency produces also severe forms of NTD. This suggests that vitamin B12 delivery to neural tissue by the CUBN/GIF pathway could play a role in the neural tube closure mechanisms. K E Y W O R D Sbirth defects, FUT2, gastric intrinsic factor, neural tube defects, 1-carbon metabolism, vitamin B12

The role of Vitamin B12 and genetic risk factors in the etiology of neural tube defects: A systematic review

“…(2018) also found a significant association between NTD risk and the T290C gene variant in the GIF gene. The GIF290C allele was found in higher prevalence among NTD infants as compared with healthy infants (Guéant‐Rodriguez et al., 2018).…”

“…Gene variants in exons 1 and 3 of the GIF gene have been found to be significantly associated with decreased vitamin B12 levels and NTD risk, respectively (Fofou‐Caillierez et al., 2019). More specifically, the T290C gene variant in the GIF gene was associated with NTD risk, and the GIF290C allele was more prevalent among NTD infants compared with healthy infants (Guéant‐Rodriguez et al., 2018). According to Chery et al.…”

Association Between MTHFR 677C>T Polymorphism and Vitamin B12 Deficiency: A Case-Control Study

“…Consequently, low levels of vitamin B12 are associated with neurological and hematological disorders such as neural tube defects, cardiovascular diseases, dementia, as well as some types of cancer (8, 16, 28, 34). However, genetic predisposition to vitamin B12 deficiency has been demonstrated in various studies (14, 15, 16, 17, 18, 19, 20, 21, 22). For in stance, vitamin B12 deficiency has been demonstrated by ABCD4 mutations and LMBRD1 mutations (35, 36).…”

“…For instance, mutations and polymorphisms in transport proteins such as transcobalamin TCN, gastric intrinsic factor GIF and metabolic enzymes such as methylenetetrahydrofolate reductase MTHFR have been associated with vitamin B12 deficiency. Other vitamin-B12 related abnormalities like homocysteinemia and neural tube defect (NTD) have also been associated with genetic variants in these genes (13, 14, 15, 16, 17, 18, 19, 20, 21, 22).…”