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The nature of the defect in cobalamin G mutation
C A Hall1, R H Lindenbaum, E Arenson
1Department of Medicine, Albany Medical College, New York.
Insights
Cobalamin G mutation (cblG) causes severe infant anemia and neurological issues. The defect lies in adenosylmethionine metabolism, impacting methionine synthesis, even with cobalamin (Cbl) treatment.
Area of Science:
- Biochemistry
- Genetics
- Pediatrics
Background:
- Cobalamin G mutation (cblG) presents as severe neonatal megaloblastic anemia.
- Neurological symptoms in cblG often show incomplete recovery despite cobalamin (Cbl) treatment.
Observation:
- Fibroblasts and lymphoblasts from cblG infants showed impaired methionine synthesis.
- These cells could internalize Cbl but failed to synthesize methylcobalamin, despite normal adenosylcobalamin synthesis.
Findings:
- cblG cells demonstrated altered methylcobalamin-dependent methyltransferase activity.
- Cells required higher adenosylmethionine concentrations and showed altered sensitivity to its suppression.
Implications:
- The cblG defect is postulated to be in adenosylmethionine metabolism.
- This metabolic error disrupts the essential synthesis of methionine from homocysteine.
Abstract:
Cobalamin G mutation (cblG) typically presents as a severe megaloblastic anemia during the first few weeks of life. The anemia responds completely to treatment with high doses of Cbl but the neurologic manifestations respond more slowly and not always completely. Cultured fibroblasts from two affected infants and virus-transformed lymphoblasts from one of the infants expressed the following: poor growth in the absence of methionine, the ability to take up and internalize Cbl bound to transcobalamin II, impaired synthesis of methionine from homocysteine, the ability to bind incoming Cbl to the respective coenzymes, but an inability to synthesize methylcobalamin in spite of a normal capacity to synthesize adenosylcobalamin. The in vitro activity of the methyltransferase dependent on methylcobalamin of cell extracts varied from low to high depending on the conditions of culture and assay. The cblG cells were unusually sensitive to the concentration of adenosylmethionine in the assay. More adenosylmethionine was required by cblG cells to achieve the same level of enzyme activity as control cells and high concentrations of adenosylmethionine did not suppress activity as in control cells. It was postulated that the defect in cblG is in the metabolism of adenosylmethionine, an essential substance for the synthesis of methionine from homocysteine.