The transcobalamin receptor knockout mouse: a model for vitamin B₁₂deficiency in the central nervous system

Abstract

The membrane receptor (TCblR/CD320) for transcobalamin (TC)-bound cobalamin (Cbl) facilitates the cellular uptake of Cbl. A genetically modified mouse model involving ablation of the CD320 gene was generated to study the effects on cobalamin homeostasis. The nonlethal nature of this knockout and the lack of systemic cobalamin deficiency point to other mechanisms for cellular Cbl uptake in the mouse. However, severe cobalamin depletion in the central nervous system (CNS) after birth (P<0.01) indicates that TCblR is the only receptor responsible for Cbl uptake in the CNS. Metabolic Cbl deficiency in the brain was evident from the increased methylmalonic acid (P<0.01-0.04), homocysteine (P<0.01), cystathionine (P<0.01), and the decreased S-adenosylmethionine/S-adenosyl homocysteine ratio (P<0.01). The CNS pathology of Cbl deficiency seen in humans may not manifest in this mouse model; however, it does provide a model with which to evaluate metabolic pathways and genes affected.

N‐homocysteinylation of tau and MAP1 is increased in autopsy specimens of Alzheimer's disease and vascular dementia

“…We studied the Cd320 KO mouse as a specific model of increased Hcy produced by a specific deficit of vitamin B12 in the brain. The ablation of the transcobalamin receptor produces a 85% decrease of B12 brain concentration and a five‐fold increase of Hcy concentration in the hippocampus . Tau homocysteinylation was increased in the CA1 layer of the hippocampus, cortex and cerebellum, compared to the wild‐type mice (Figure A).…”

The clinical presentation of cobalamin‐related disorders: From acquired deficiencies to inborn errors of absorption and intracellular pathways

“…The CD320 knockout mouse shows behavioral and morphological changes (anxiety, learning and memory deficits; decreased brain mass) and serves as a model for brain pathology in intracellular Cbl deprivation. In a single case of a 7‐week‐old boy with CD320 mutations, his bilateral central retinal artery occlusions were attributed to elevated tHcy concentrations of 17 μmol/L.…”

Maternofetal transport of vitamin B12: role of TCblR/CD320and megalin

“…The TCblR/ CD320 KO is not associated with embryonic lethality, and the homozygous pups are carried to term and appear normal at birth. These mice do not develop systemic Cbl deficiency; they grow normally, and homozygous mice reproduce normally (4). At birth, these mice have normal Cbl levels in all tissues but start losing Cbl in the brain gradually to undetectable levels in a matter of months (4).…”

“…These mice do not develop systemic Cbl deficiency; they grow normally, and homozygous mice reproduce normally (4). At birth, these mice have normal Cbl levels in all tissues but start losing Cbl in the brain gradually to undetectable levels in a matter of months (4). This results in elevated TC‐Cbl in blood without a significant decrease in Cbl in the liver and kidneys.…”