A novel mouse model for genetic variation in 10-formyltetrahydrofolate synthetase exhibits disturbed purine synthesis with impacts on pregnancy and embryonic development
Rattachement africain : ca, gb, us. Niveau de preuve : code pays fourni par la source.
Le résumé fourni par la source
Genetic variants in one-carbon folate metabolism have been identified as risk factors for disease because they may impair the production or use of one-carbon folates required for nucleotide synthesis and methylation. p.R653Q (1958G>A) is a single-nucleotide polymorphism (SNP) in the 10-formyltetrahydrofolate (formylTHF) synthetase domain of the trifunctional enzyme MTHFD1; this domain produces the formylTHF which is required for the de novo synthesis of purines. Approximately 20% of Caucasians are homozygous for the Q allele. MTHFD1 p.R653Q has been proposed as a risk factor for neural tube defects (NTDs), congenital heart defects (CHDs) and pregnancy losses. We have generated a novel mouse model in which the MTHFD1 synthetase activity is inactivated without affecting protein expression or the other activities of this enzyme. Complete loss of synthetase activity (Mthfd1S(-/-)) is incompatible with life; embryos die shortly after 10.5 days gestation, and are developmentally delayed or abnormal. The proportion of 10-formylTHF in the plasma and liver of Mthfd1S(+/-) mice is reduced (P < 0.05), and de novo purine synthesis is impaired in Mthfd1S(+/-) mouse embryonic fibroblasts (MEFs, P < 0.005). Female Mthfd1S(+/-) mice had decreased neutrophil counts (P < 0.05) during pregnancy and increased incidence of developmental defects in embryos (P = 0.052). These findings suggest that synthetase deficiency may lead to pregnancy complications through decreased purine synthesis and reduced cellular proliferation. Additional investigation of the impact of synthetase polymorphisms on human pregnancy is warranted.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- A novel mouse model for genetic variation in 10-formyltetrahydrofolate synthetase exhibits disturbed purine synthesis with impacts on pregnancy and embryonic development
- Date Crossref
- 23/05/2013
- Éditeur
- Oxford University Press (OUP)
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Montreal Children's Hospital pays non établi dans la noticeÉtablissement de santé
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McGill University Health Centre Departments of Human Genetics and Pediatrics pays non établi dans la noticeÉtablissement de santé
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University College London Institute of Child Health pays non établi dans la noticeUniversité ou école supérieure
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Baylor University pays non établi dans la noticeUniversité ou école supérieure
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Cornell University Division of Nutritional Sciences and Genomics pays non établi dans la noticeUniversité ou école supérieure
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Medical University of South Carolina Department of Biochemistry and Molecular Biology pays non établi dans la noticeUniversité ou école supérieure
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McGill University pays non établi dans la noticeUniversité ou école supérieure
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Institute of Metabolic Disease pays non établi dans la noticeStructure de recherche
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Baylor Research Institute pays non établi dans la noticeStructure de recherche
Montreal Children's Hospital, Departments of Human Genetics and Pediatrics — McGill University Health Centre et Institute of Child Health — University College London, avec 6 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.