Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: GULOP
SNOMEDCT: 76169001; ICD10CM: E54; DO: 13724;
Cytogenetic location: 8p21.1 Genomic coordinates (GRCh38): 8:27,500,001-29,000,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8p21.1 | Scurvy | 3 |
As far as is known, all members of the human species lack the ability to synthesize ascorbic acid because man, unlike most other mammals, does not possess the enzyme L-gulonolactone oxidase (EC 1.1.3.8). As Stone (1967) pointed out, hypoascorbemia is an inborn error of metabolism. Borrowing a term from the blood groups, we might say that it is a 'public' inborn error of metabolism. The mechanism whereby an organism loses a particular metabolic function which is of no use in a particular environment was discussed by King and Jukes (1969). The accumulation of random mutations in the gene for the relevant enzyme might be expected to destroy the functional capacity of the enzyme, most mutations being disruptive. If the enzyme is not required in the particular environment, the constraint of selection is removed. Primates and the guinea pig, by this hypothesis, have lost the capacity to synthesize ascorbic acid because of the adequacy of dietary intake. An intraspecies example of this phenomenon may be the loss of adult intestinal lactase in people who do not consume milk. Nishikimi and Udenfriend (1976) showed that primate and guinea pig liver contains no cross-reacting material for L-gulono-gamma-lactone oxidase. Nishikimi et al. (1988) isolated a cDNA encoding L-gulono-gamma-lactone oxidase of the rat. Northern blot hybridization using the cDNA as a probe demonstrated that guinea pigs lack mRNA for this enzyme. Nevertheless, existence of a DNA sequence related to this enzyme was demonstrated in the genome of both the guinea pig and the human by Southern blot hybridization. The degree of hybridization in the human was less than in the animals possessing the enzyme, suggesting that the human L-gulono-gamma-lactone oxidase gene has diverged more rapidly than the genes of ascorbic acid-synthesizing species. This hypothesis was confirmed by a comparison of a partial nucleotide sequence of the human gene with that of the rat gene. The sequences in the guinea pig and human genomes may represent the remnants of the gene for the enzyme that was once active but became nonfunctional during the course of evolution.
Nishikimi et al. (1992) demonstrated that guinea pigs, which, like humans and other primates, cannot synthesize vitamin C, contain a nucleotide sequence of a once active gulonolactone oxidase gene which cross-hybridized to a rat cDNA; this despite the fact that no detectable gulonolactone oxidase-specific mRNA or cross-reactive protein was recognizable by anti-rat GLO rabbit antibody. Comparison of the guinea pig gene with the rat gene demonstrated absence of regions corresponding to exons 1 and 5 as well as other deletions and nonconformance to the GT/AG rule at one of the putative intron/exon boundaries. There were also a large number of mutations in the amino acid-coding regions of the guinea pig sequence, many of which led to nonconservative amino acid changes, and there were 3 stop codons as well. On the basis of the neutral theory of evolution, the date of the loss of the L-gulono-gamma-lactone oxidase in the ancestors of the guinea pig was roughly calculated to be less than 20 million years ago.
The disorder of osteogenesis present in the Shionogi rat represents a susceptibility to scurvy because of lack of L-gulono-gamma-lactone oxidase. Kawai et al. (1992) demonstrated that the mutant cDNA has a single base mutation from G to A at nucleotide 182, which changes amino acid 61 from cys to tyr. To test the effect of the cys61-to-tyr mutation, they transfected COS-1 cells with a vector containing the mutant cDNA and showed that the amino acid substitution both decreased the amount of immunologically detectable protein and the level of enzyme activity to about one-tenth of their normal values, while it did not affect the amount of mRNA produced in the transfected cells. Thus, scurvy is a rare inborn error of metabolism in the rat.
Nishikimi et al. (1994) isolated a segment of the nonfunctional L-gulono-gamma-lactone oxidase gene from a human genomic library and mapped it to 8p21.1 by spot blot hybridization using flow-sorted human chromosomes and fluorescence in situ hybridization. The isolated segment represented the 3-prime part of the gene, where the regions corresponding to exons 7, 9, 10, and 12 of the rat gene remained with probable deletion of the regions corresponding to exons 8 and 11. A large number of other mutations were found.
Levine et al. (1996) performed an in-hospital depletion-repletion study of the relationship between vitamin C dose and steady-state plasma concentration. Seven healthy volunteers were hospitalized for 4 to 6 months and consumed a diet containing less than 5 mg of vitamin C daily. Steady-state plasma and tissue concentrations were determined at 7 daily doses of vitamin C from 30 to 2,500 mg. Vitamin C steady-state plasma concentrations as a function of dose displayed sigmoid kinetics. The steep portion of the curve occurred between the 30- and 100-mg daily dose, the then-current recommended daily allowance (RDA) of 60 mg was on the lower third of the curve, the first dose beyond the sigmoid portion of the curve was 200 mg daily, and complete plasma saturation occurred at 1,000 mg daily. No vitamin C was excreted in the urine of 6 of 7 volunteers until the 100-mg dose was reached. At single doses of 500 mg and higher, bioavailability declined and the absorbed amount was excreted. Oxalate and urate excretion were elevated at 1,000 mg of vitamin C daily compared to lower doses. Based on these data, Levine et al. (1996) recommended that the RDA of vitamin C be increased to 200 mg daily, which can be obtained from fruits and vegetables. Safe doses of vitamin C are less than 1,000 mg daily, and vitamin C daily doses above 400 mg have no evident value.
The absorption of vitamin C into the body and its distribution to organs requires the sodium-coupled vitamin C transporters SVCT1 (SLC23A2; 603790) and SVCT2 (SLC23A1; 603791). SVCT1 is largely confined to epithelial surfaces involved in bulk transport, such as those of the intestine and kidney, whereas SVCT2 appears to account for tissue-specific uptake of vitamin C. SVCT2 expression is widespread, occurring in neurons, the endocrine system, bone, and other tissues (Hediger, 2002). Sotiriou et al. (2002) demonstrated that SLC23A1 is essential for transport of vitamin C into the brain and for perinatal survival. Previously, the only proven requirement for ascorbic acid was in preventing scurvy, presumably because vitamin C is a cofactor for hydroxylases required for posttranslational modifications that stabilize collagen.
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Nishikimi, M., Fukuyama, R., Minoshima, S., Shimizu, N., Yagi, K. Cloning and chromosomal mapping of the human nonfunctional gene for L-gulono-gamma-lactone oxidase, the enzyme for L-ascorbic acid biosynthesis missing in man. J. Biol. Chem. 269: 13685-13688, 1994. [PubMed: 8175804]
Nishikimi, M., Kawai, T., Yagi, K. Guinea pigs possess a highly mutated gene for L-gulono-gamma-lactone oxidase, the key enzyme for L-ascorbic acid biosynthesis missing in this species. J. Biol. Chem. 267: 21967-21972, 1992. [PubMed: 1400507]
Nishikimi, M., Koshizaka, T., Ozawa, T., Yagi, K. Occurrence in humans and guinea pigs of the gene related to their missing enzyme L-gulono-gamma-lactone oxidase. Arch. Biochem. Biophys. 267: 842-846, 1988. [PubMed: 3214183] [Full Text: https://doi.org/10.1016/0003-9861(88)90093-8]
Nishikimi, M., Udenfriend, S. Immunologic evidence that the gene for L-gulono-gamma-lactone oxidase is not expressed in animals subject to scurvy. Proc. Nat. Acad. Sci. 73: 2066-2068, 1976. [PubMed: 819930] [Full Text: https://doi.org/10.1073/pnas.73.6.2066]
Pauling, L. Evolution and the need for ascorbic acid. Proc. Nat. Acad. Sci. 67: 1643-1648, 1970. [PubMed: 5275366] [Full Text: https://doi.org/10.1073/pnas.67.4.1643]
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