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

Abstract

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.

• Authors: David J Bernard, Faith J Pangilinan, Jun Cheng, Anne M Molloy, Lawrence C Brody
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 27 Issue 20 Pg. 3627-3640 (10 15 2018) ISSN: 1460-2083 [Electronic] England
• PMID: 30124850 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• Receptors, Cell Surface
• transcobalamin receptor

Topics

• Anemia (etiology)
• Animals
• Diet
• Disease Models, Animal
• Female
• Male
• Mice
• Mice, Knockout
• Receptors, Cell Surface (genetics)
• Reproduction
• Vitamin B 12 Deficiency (complications, genetics, metabolism, physiopathology)