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Am J Hum Genet. 1988 Oct; 43(4): 414–421.
PMCID: PMC1715503

Intermediate homocysteinemia: a thermolabile variant of methylenetetrahydrofolate reductase.


A "newly detected" variant of methylenetetrahydrofolate (MTHF) reductase (E.C. deficiency associated with an 8-15-fold increase in plasma total homocysteine was discovered in two unrelated patients who had subnormal serum folate. However, the homocysteinemia was corrected by oral folic acid supplement. When MTHF reductase activities in lymphocyte extracts before and after heat treatment at 46 C for 5 min were compared, there was a consistent difference in heat stability between the enzyme from the controls and that from the patients. The mean residual activities after heat treatment were 37.0% (34.1%-42.6%) in the controls and 15.2% and 15.1% in the two patients, respectively. Two obligate heterozygotes for severe MTHF reductase deficiency had residual activities of 39.6% and 37.7%. A similar difference in thermostability was demonstrated in cultured skin fibroblasts and lymphoblasts. Studies with a mixture of lymphoblast extracts from a control and a patient and with partially purified enzyme suggested that the thermostability was an independent characteristic of MTHF reductase. These observations provided evidence of a hitherto undescribed mutant MTHF reductase in our two patients with intermediate homocysteinemia. Unlike previously reported patients with MTHF reductase deficiency, there was no apparent clinical problem related to the abnormal folate or homocysteine metabolism during infancy or childhood in these two subjects, but one of them had vascular disorders in adulthood. The observations in these two subjects suggested that a moderate deficiency of MTHF reductase might be associated with vascular disorders in adult life.

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Selected References

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  • Cooper BA, Rosenblatt DS. Inherited defects of vitamin B12 metabolism. Annu Rev Nutr. 1987;7:291–320. [PubMed]
  • Dunn RT, Foster LB. Radioassay of serum folate. Clin Chem. 1973 Oct;19(10):1101–1105. [PubMed]
  • Erbe RW. Genetic aspects of folate metabolism. Adv Hum Genet. 1979;9:293–369. [PubMed]
  • Fabbro D, Desnick RJ, Grabowski GA. Gaucher disease: genetic heterogeneity within and among the subtypes detected by immunoblotting. Am J Hum Genet. 1987 Jan;40(1):15–31. [PMC free article] [PubMed]
  • Jondal M, Holm G, Wigzell H. Surface markers on human T and B lymphocytes. I. A large population of lymphocytes forming nonimmune rosettes with sheep red blood cells. J Exp Med. 1972 Aug 1;136(2):207–215. [PMC free article] [PubMed]
  • Kang SS, Wong PW, Becker N. Protein-bound homocyst(e)ine in normal subjects and in patients with homocystinuria. Pediatr Res. 1979 Oct;13(10):1141–1143. [PubMed]
  • Kang SS, Wong PW, Curley K. The effect of D-penicillamine on protein-bound homocyst(e)ine in homocystinurics. Pediatr Res. 1982 May;16(5):370–372. [PubMed]
  • Kang SS, Wong PW, Cook HY, Norusis M, Messer JV. Protein-bound homocyst(e)ine. A possible risk factor for coronary artery disease. J Clin Invest. 1986 May;77(5):1482–1486. [PMC free article] [PubMed]
  • Kang SS, Wong PW, Norusis M. Homocysteinemia due to folate deficiency. Metabolism. 1987 May;36(5):458–462. [PubMed]
  • Kang SS, Wong PW, Zhou JM, Sora J, Lessick M, Ruggie N, Grcevich G. Thermolabile methylenetetrahydrofolate reductase in patients with coronary artery disease. Metabolism. 1988 Jul;37(7):611–613. [PubMed]
  • Kanwar YS, Manaligod JR, Wong PW. Morphologic studies in a patient with homocystinuria due to 5, 10-methylenetetrahydrofolate reductase deficiency. Pediatr Res. 1976 Jun;10(6):598–609. [PubMed]
  • Kutzbach C, Stokstad EL. Mammalian methylenetetrahydrofolate reductase. Partial purification, properties, and inhibition by S-adenosylmethionine. Biochim Biophys Acta. 1971 Dec 15;250(3):459–477. [PubMed]
  • LOWRY OH, ROSEBROUGH NJ, FARR AL, RANDALL RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed]
  • Mudd SH, Uhlendorf BW, Freeman JM, Finkelstein JD, Shih VE. Homocystinuria associated with decreased methylenetetrahydrofolate reductase activity. Biochem Biophys Res Commun. 1972 Jan 31;46(2):905–912. [PubMed]
  • Rosenblatt DS, Erbe RW. Methylenetetrahydrofolate reductase in cultured human cells. I. Growtha and metabolic studies. Pediatr Res. 1977 Nov;11(11):1137–1141. [PubMed]
  • Rudzki Z, Nazaruk M, Kimber RJ. The clinical value of the radioassay of serum folate. J Lab Clin Med. 1976 May;87(5):859–867. [PubMed]
  • Smolin LA, Benevenga NJ. Accumulation of homocyst(e)ine in vitamin B-6 deficiency: a model for the study of cystathionine beta-synthase deficiency. J Nutr. 1982 Jul;112(7):1264–1272. [PubMed]
  • Wong PW, Justice P, Berlow S. Detection of homozygotes and heterozygotes with methylenetetrahydrofolate reductase deficiency. J Lab Clin Med. 1977 Aug;90(2):283–288. [PubMed]
  • Wong PW, Justice P, Hruby M, Weiss EB, Diamond E. Folic acid nonresponsive homocystinuria due to methylenetetrahydrofolate reductase deficiency. Pediatrics. 1977 May;59(5):749–756. [PubMed]

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