Mice lacking the transcobalamin-vitamin B12 receptor, CD320, suffer from anemia and reproductive deficits when fed vitamin B12-deficient diet.

In humans, poor nutrition, malabsorption and variation in cobalamin (vitamin B12) metabolic genes are associated with hematological, neurological and developmental pathologies. Cobalamin is transported from blood into tissues via the transcobalamin (TC) receptor encoded by the CD320 gene. We created mice carrying a targeted deletion of the mouse ortholog, Cd320. Knockout (KO) mice lacking this TC receptor have elevated levels of plasma methylmalonic acid and homocysteine but are otherwise healthy, viable, fertile and not anemic. To challenge the Cd320 KO mice we maintained them on a vitamin B12-deficient diet. After 5 weeks on this diet, reproductive failure develops in Cd320 KO females but not males. In vitro, homozygous Cd320 KO embryos from cobalamin-deficient Cd320 KO dams develop normally to embryonic day (E) 3.5, while in vivo, few uterine decidual implantation sites are observed at E7.5, suggesting that embryos perish around the time of implantation. Dietary restriction of vitamin B12 induces a severe macrocytic anemia in Cd320 KO mice after 10-12 months while control mice on this diet are anemia-free up to 2 years. Despite the severe anemia, cobalamin-deficient KO mice do not exhibit obvious neurological symptoms. Our results with Cd320 KO mice suggest that an alternative mechanism exists for mice to transport cobalamin independent of the Cd320 encoded receptor. Our findings with deficient diet are consistent with historical and epidemiological data suggesting that low vitamin B12 levels in humans are associated with infertility and developmental abnormalities. Our Cd320 KO mouse model is an ideal model system for studying vitamin B12 deficiency.

The MTHFR 1298CC and 677TT genotypes have opposite associations with red cell folate levels.

Individuals homozygous for the thermolabile variant (677TT) of methylenetetrahydrofolate reductase exhibit reduced folate status as evidenced by a drop in the biomarker red cell folate (RCF) compared to those who carry at least one 677C allele. We now report that a different polymorphism in the same enzyme, namely 1298A>C, is associated with increased RCF levels. Thus, these two common polymorphisms change a metabolic phenotype in opposite directions suggesting that their cancer protective associations are by different mechanisms.

MTHFD1 R653Q polymorphism is a maternal genetic risk factor for severe abruptio placentae.

This study examined the relationship between folate/homocysteine-related genetic polymorphisms: MTHFD1 1958G --> A (R653Q), MTHFR 677C --> T (A222V), MTHFR 1298A --> C (E429A), and risk of severe abruptio placentae. We genotyped 62 women with a pregnancy history complicated by severe abruptio placentae and 184 control pregnancies. Analysis of the MTHFD1 1958G --> A (R653Q) polymorphism showed increased frequency of the 'QQ' homozygote genotype in pregnancies affected by severe abruptio placentae compared to control pregnancies (odds ratio 2.85 (1.47-5.53), P = 0.002). In contrast to previous reports, the MTHFR polymorphisms 677C --> T (A222V) and 1298A --> C (E429A) were not associated with abruptio placentae risk in our cohort, when analyzed either independently or in combination. We conclude that women who are 'QQ' homozygote for the MTHFD1 1258G --> A (R653Q) polymorphism are almost three times more likely to develop severe abruptio placentae during their pregnancy than women who are 'RQ' or 'RR.'