Defects in cobalamin (B12) metabolism
Species Homo sapiens
Cobalamin (Cbl, vitamin B12) is a nutrient essential for normal functioning of the brain and nervous system and for the formation of blood. Cbl-dependent methionine synthase (MTR) is required for conversion of 5-methyltetrahydrofolate (metTHF) to tetrahydrofolate (THF), in addition to its role in conversion of homocysteine to methionine. In Cbl deficiency, and in inborn errors of Cbl metabolism that affect function of methionine synthase, inability to regenerate THF from metTHF results in decreased function of folate-dependent reactions that are involved in 2 steps of purine biosynthesis and thymidylate synthesis. Cbl deficiency results in hyperhomocysteinemia (due to defects in the conversion of homocysteine to methionine which requires Cbl as a cofactor) and increased levels of methylmalonic acid (MMA). Methionine is used in myelin production, protein, neurotransmitter, fatty acid and phospholipid production and DNA methylation. Symptoms of Cbl deficiency are bone marrow promegaloblastosis (megaloblastic anemia) due to the inhibition of DNA synthesis (specifically purines and thymidine) and neurological symptoms. The defective genes involved in Cbl deficiencies are described below (Froese & Gravel 2010, Nielsen et al. 2012, Whitehead 2006, Watkins & Rosenblatt 2011, Fowler 1998).
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