Dataset Information

Crooked tail (Cd) model of human folate-responsive neural tube defects is mutated in Wnt coreceptor lipoprotein receptor-related protein 6.

ABSTRACT: A cranial neural tube defect in Crooked tail (Cd) mice is prevented with prenatal dietary folic acid Cd positional cloning reveals a missense mutation of a highly conserved amino acid in the low density lipoprotein receptor-related protein 6 (Lrp6), a coreceptor required for Wnt canonical signaling. Molecular modeling predicts that Lrp6(Cd) alters a hinge region of the second YWTD beta-propeller domain. Mutant LRP6 binds to Wnt and Dickkopf1 (Dkk1) but not Mesd1, and Dkk1 cannot antagonize Wnt in Cd/Cd cells, resulting in hyperactivity. NIH 3T3 cells transfected with a mutant Lrp6 plasmid resist Dkk1 antagonism much like Cd/+ cells, confirming the significance of the mutation. The Lrp6 mutation in Cd mice provides evidence for a functional connection between Wnt signaling and folate rescue of neural tube defects.

SUBMITTER: Carter M

PROVIDER: S-EPMC1200260 | biostudies-literature | 2005 Sep

REPOSITORIES: biostudies-literature

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Crooked tail (Cd) model of human folate-responsive neural tube defects is mutated in Wnt coreceptor lipoprotein receptor-related protein 6.

Carter Michelle M Chen Xu X Slowinska Bozena B Minnerath Sharon S Glickstein Sara S Shi Lei L Campagne Fabien F Weinstein Harel H Ross M Elizabeth ME

Proceedings of the National Academy of Sciences of the United States of America 20050826 36

A cranial neural tube defect in Crooked tail (Cd) mice is prevented with prenatal dietary folic acid Cd positional cloning reveals a missense mutation of a highly conserved amino acid in the low density lipoprotein receptor-related protein 6 (Lrp6), a coreceptor required for Wnt canonical signaling. Molecular modeling predicts that Lrp6(Cd) alters a hinge region of the second YWTD beta-propeller domain. Mutant LRP6 binds to Wnt and Dickkopf1 (Dkk1) but not Mesd1, and Dkk1 cannot antagonize Wnt i ...[more]

PMID: 16126904

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Project description:Periconceptional folic acid use can often prevent neural tube defects (NTDs). Variants of genes involved in folate metabolism in mothers and children have been associated with occurrence of NTDs. We identified Irish families with individuals affected by neural tube defects. In these families, we observed that neural tube defects and birth defects overall occurred at a higher rate in the maternal lineage compared with the paternal lineage. The goal of this study was to look for evidence for genetic effects that could explain the discrepancy in the occurrence of these birth defects in the maternal vs. paternal lineage. We genotyped blood samples from 322 individuals from NTD-affected Irish families, identified through their membership in spina bifida associations. We looked for differences in distribution in maternal vs. paternal lineages of five genetic polymorphisms: the DHFR 19 bp deletion, MTHFD1 1958G>A, MTHFR 1298A>C, MTHFR 677C>T, and SLC19A1 80A>G. In addition to looking at genotypes individually, we determined the number of genotypes associated with decreased folate metabolism in each relative ("risk genotypes") and compared the distribution of these genotypes in maternal vs. paternal relatives. Overall, maternal relatives had a higher number of genotypes associated with lower folate metabolism than paternal relatives (p = 0.017). We expected that relatives would share the same risk genotype as the individuals with NTDs and/or their mothers. However, we observed that maternal relatives had an over-abundance of any risk genotype, rather than one specific genotype. The observed genetic effects suggest an epigenetic mechanism in which decreased folate metabolism results in epigenetic alterations related to the increased rate of NTDs and other birth defects seen in the maternal lineage. Future studies on the etiology of NTDs and other birth defects could benefit from including multigenerational extended families, in order to explore potential epigenetic mechanisms.

Project description:ObjectiveTo determine an optimal population red blood cell (RBC) folate concentration for the prevention of neural tube birth defects.DesignBayesian model.SettingData from two population based studies in China.Participants247,831 participants in a prospective community intervention project in China (1993-95) to prevent neural tube defects with 400 μg/day folic acid supplementation and 1194 participants in a population based randomized trial (2003-05) to evaluate the effect of folic acid supplementation on blood folate concentration among Chinese women of reproductive age.InterventionFolic acid supplementation (400 μg/day).Main outcome measuresEstimated RBC folate concentration at time of neural tube closure (day 28 of gestation) and risk of neural tube defects.ResultsRisk of neural tube defects was high at the lowest estimated RBC folate concentrations (for example, 25.4 (95% uncertainty interval 20.8 to 31.2) neural tube defects per 10,000 births at 500 nmol/L) and decreased as estimated RBC folate concentration increased. Risk of neural tube defects was substantially attenuated at estimated RBC folate concentrations above about 1000 nmol/L (for example, 6 neural tube defects per 10,000 births at 1180 (1050 to 1340) nmol/L). The modeled dose-response relation was consistent with the existing literature. In addition, neural tube defect risk estimates developed using the proposed model and population level RBC information were consistent with the prevalence of neural tube defects in the US population before and after food fortification with folic acid.ConclusionsA threshold for "optimal" population RBC folate concentration for the prevention of neural tube defects could be defined (for example, approximately 1000 nmol/L). Population based RBC folate concentrations, as a biomarker for risk of neural tube defects, can be used to facilitate evaluation of prevention programs as well as to identify subpopulations at elevated risk for a neural tube defect affected pregnancy due to folate insufficiency.

Dataset Information

Crooked tail (Cd) model of human folate-responsive neural tube defects is mutated in Wnt coreceptor lipoprotein receptor-related protein 6.

Publications

Crooked tail (Cd) model of human folate-responsive neural tube defects is mutated in Wnt coreceptor lipoprotein receptor-related protein 6.

Similar Datasets

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