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The TCblR/CD320 KO mouse: A model to study the effects of vitamin B12 deficiency
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Quadros, Edward V.
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Spring 2017
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2017-05-01
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Doctoral Dissertation
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Vitamin B12 (Cobalamin, Cbl) deficiency causes megaloblastic anemia and neuropsychiatric disorders in humans. While the pathways leading megaloblastic anemia are well defined, the metabolic basis of neuropathology is unknown. Infants born with congenital gene defects in TC or TCblR/CD320 have normal Cbl levels at birth which are presumed to be compensated by the mother. After birth, these infants become Cbl deficient and develop hematologic/neurologic complications. It is not known how the infants with TCblR/CD320 gene defects obtain Cbl from the mother in utero.
Studying the TCblR/CD320 KO mouse, our results showed that in absence of TCblR/CD320, megalin provides an alternate mechanism for the maternofetal transport of Cbl. After birth, however, megalin in the brain and spinal cord (SC) gets restricted to the nucleus making it unavailable to transport Cbl, causing its deficiency.
Post development, TCblR/CD320 KO mouse develops neurologic alterations as observed in Cbl deficient patients. The KO mouse showed elevated anxiety and deficits in learning of a spatial memory task along with, impaired early expression of hippocampal long-term potentiation and reduced levels of GluR1. The TCblR/CD320 KO mouse also showed myelin loss in the SC and sciatic nerve, consequently, increased latency to thermal nociception. These results were further supported by lipidome and transcriptome analysis.
This study provides insight into how Cbl is transported from mother to fetus and how Cbl deficiency occurs after birth which causes neurologic deficits in the KO mouse, like humans. These studies, along with elevated homocysteine, indicate metabolic stress as a potential cause of this phenotype.
Citation
Arora, K. (2017) The TCblR/CD320 KO mouse: A model to study the effects of vitamin B12 deficiency. [Doctoral dissertation, SUNY Downstate Health Sciences University]. SUNY Open Access Repository. https://soar.suny.edu/handle/20.500.12648/15873
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Doctoral Dissertation