Vitamin B12—Folate Interrelations

Das, K. C.; Herbert, Victor

doi:10.1016/s0308-2261(21)00116-8

Cited by 60 publications

(1 citation statement)

References 111 publications

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“…Recently, the possibility was suggested from familial analysis of patients that the fragile site at band q27 on the X chromosome in affected persons is a spot influencing meiotic recombination (38). In patients with megaloblastic anemia due to vitamin B12 or folate deficiency, which leads to thymidylate stress, unusual chromosome aberrations and cytogenetic alterations are observed (14). It is therefore probable that genetic and cytogenetic stability could be affected by the combination of both a peculiar type of DNA structure and certain deviations in the activity of thymidylate biosynthesis in mammalian cells as demonstrated in the present study.…”

Section: Discussionmentioning

confidence: 99%

Induction, by Thymidylate Stress, of Genetic Recombination as Evidenced by Deletion of a Transferred Genetic Marker in Mouse FM3A Cells

Ayusawa

Koyama

Shimizu

et al. 1986

Molecular and Cellular Biology

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Studies were made on the genetic consequences of methotrexate-directed thymidylate stress, focusing attention on a human thymidylate synthase gene that was introduced as a heterologous genetic marker into mouse thymidylate synthase-negative mutant cells. Thymidylate stress induced thymidylate synthase-negative segregants with concomitant loss of human thymidylate synthase activity with frequencies 1 to 2 orders of magnitude higher than the uninduced spontaneous level in some but not all transformant lines. Induction of the segregants was suppressed almost completely by cycloheximide and partially by caffeine. Thymidylate stress did not, however, induce mutations, as determined by measuring resistance to ouabain or 6-thioguanine. Thymidylate synthase-negative segregants were also induced by other means such as bromodeoxyuridine treatment and X-ray irradiation. In each of the synthase-negative segregants induced by thymidylate stress, a DNA segment including almost the whole coding region of the transferred human thymidylate synthase gene was deleted in a very specific manner, as shown by Southern blot analysis with a human Alu sequence and a human thymidylate synthase cDNA as probes. In the segregants that emerged spontaneously at low frequency, the entire transferred genetic marker was lost. In the segregants induced by X-ray irradiation, structural alterations of the genetic marker were random. These results show that thymidylate stress is a physiological factor that provokes the instability of this exogenously incorporated DNA in some specific manner and produces nonrandom genetic recombination in mammalian cells.

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Section: Discussionmentioning

confidence: 99%

Induction, by Thymidylate Stress, of Genetic Recombination as Evidenced by Deletion of a Transferred Genetic Marker in Mouse FM3A Cells

Ayusawa

Koyama

Shimizu

et al. 1986

Molecular and Cellular Biology

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In vitro DNA synthesis by megaloblastic bone marrow: Effect of folates and cobalamins on thymidine incorporation and de novo thymidylate synthesis

Das¹,

Herbert²

1989

American J Hematol

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The de novo pathway of thymidylate synthesis (i.e., methylation of dUMP to dTMP) is directly folate dependent and indirectly vitamin B12 (cobalamins) dependent. In deficiency of these vitamins, this pathway is impaired, and exogenous deoxyuridine (dU) fails to suppress adequately in vitro incorporation of [3H]thymidine (3H-TdR) into DNA via the salvage pathway (i.e., abnormal dU suppression). This abnormality is corrected by the addition of folate compounds (analogues) and/or vitamin B12 depending on the nature of the underlying deficiency. We studied the effects of addition of PteGlu, 5-methyl THF (5-CH3-FH4), 5-formyl-THF (5-CHO-FH4), and hydroxy-cobalamin (OH-cbl) on 3H-TdR incorporation into DNA and thymidine kinase activity (salvage pathway), and on [3H]deoxyuridine (3H-dU) incorporation and dU suppression values (de novo pathway) in cultures of normal and megaloblastic bone marrows. The results showed that 3H-TdR incorporation into DNA and the salvage enzyme, thymidine kinase, activity were greater and 3H-dU incorporation into DNA less in megaloblastic cells as compared with normal cells. The addition of folates significantly reduced 3H-TdR incorporation and thymidine kinase activity and enhanced 3H-dU incorporation in folate and vitamin B12-deficient cells except that 5-CH3-FH4 had no effect on vitamin B12-deficient cells. None of these additives had any significant effect on normal cells. This study also showed that the addition of the deficient vitamin(s) to the "control tubes" in the dU suppression test is inappropriate, as these vitamins may at least partially correct the defect in cellular DNA synthesis caused by the deficiencies of these vitamins and may mask these deficiencies in the results of the in vitro correction of the dU suppression abnormalities in mild cases of megaloblastic anemia.

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Eighteen‐year follow‐up of a patient with cobalamin F disease (cblF): Report and review

Alfadhel

Lillquist

Davis

et al. 2011

American J of Med Genetics Pt A

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Cobalamin F disease (cblF) is a rare disorder of intracellular cobalamin metabolism resulting in failure to thrive, recurrent stomatitis, skin rash, megaloblastic anemia, hypotonia, seizures, and intellectual disability. Data on long-term outcomes are not available. We report on the outcome of a patient with cblF disease with a frameshift mutation in the LMBRD1 gene after 18 years of intramuscular hydroxycobalamin treatment.

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Vitamin B12—Folate Interrelations

Cited by 60 publications

References 111 publications

Induction, by Thymidylate Stress, of Genetic Recombination as Evidenced by Deletion of a Transferred Genetic Marker in Mouse FM3A Cells

Induction, by Thymidylate Stress, of Genetic Recombination as Evidenced by Deletion of a Transferred Genetic Marker in Mouse FM3A Cells

In vitro DNA synthesis by megaloblastic bone marrow: Effect of folates and cobalamins on thymidine incorporation and de novo thymidylate synthesis

Eighteen‐year follow‐up of a patient with cobalamin F disease (cblF): Report and review

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