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Gene Review

HGD  -  homogentisate 1,2-dioxygenase

Homo sapiens

Synonyms: AKU, HGO, Homogentisate 1,2-dioxygenase, Homogentisate oxygenase, Homogentisic acid oxidase, ...
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Disease relevance of HGD


High impact information on HGD

  • We show that HGO maps to the same location described for AKU, illustrate that HGO harbours missense mutations that cosegregate with the disease, and provide biochemical evidence that at least one of these missense mutations is a loss-of-function mutation [1].
  • Glucose production (HGO), glucose utilization (Rd) [3-3H]glucose, and glucose oxidation and lipid oxidation (LO) (indirect calorimetry) were determined [6].
  • We conclude that, in a late phase of hypoglycemia, the indirect effects of catecholamines (lipolysis mediated) account for at least approximately 50% of the adrenergic contribution to increased HGO, and approximately 85% of suppressed Rd [6].
  • Homogentisate dioxygenase (HGO) cleaves the aromatic ring during the metabolic degradation of Phe and Tyr [7].
  • The active site iron ion is coordinated near the interface between subunits in the HGO trimer by a Glu and two His side chains [7].

Chemical compound and disease context of HGD


Biological context of HGD

  • Herein we describe haplotype and mutational analyses of HGO in seven new AKU pedigrees [8].
  • We also report characterization of five polymorphic sites in HGO and describe the haplotypic associations of alleles at these sites in normal and AKU chromosomes [2].
  • We identified 12 novel mutations: 8 (E42A, W97G, D153G, S189I, I216T, R225H, F227S, and M368V) missense mutations that result in amino acid substitutions at positions conserved in HGO in different species, 1 (F10fs) frameshift mutation, 2 intronic mutations (IVS9-56G-->A, IVS9-17G-->A), and 1 splice-site mutation (IVS5+1G-->T) [2].
  • The human HGO gene spans 54,363 bp and codes for a 1715-nt-long transcript that is split into 14 exons ranging from 35 to 360 bp [9].
  • The HGO transcription start site was determined by primer extension [9].

Anatomical context of HGD

  • We report that sequences from -1074 to +89 bp (relative to the HGO transcription start site) are sufficient to promote transcription of a CAT reporter gene in human liver cells and that this fragment contains putative binding sites for liver-enriched transcription factors that might be involved in the regulation of HGO expression in liver [9].
  • AIMS: To assess the involvement of the recently identified human homogentisate 1,2-dioxygenase gene (HGO) in alkaptonuria (AKU) in two unrelated patients with ochronosis of the conjunctiva, sclera, and cornea [13].
  • To elucidate the role of COX-2 in esophageal carcinogenesis, we examined the expression of this enzyme in normal squamous epithelium (n = 42), squamous dysplasia [high-grade dysplasia (HGD, n = 41; low-grade dysplasia (LGD, n = 33)]; carcinoma in situ (n = 16), mucosal invasive carcinoma (n = 18), and advanced SCC (n = 45) [14].
  • Gastric dysplasia (high-grade, HGD, and low-grade, LGD) and normal mucosa were tested for anti-p53, anti-Ki-67 and anti-PCNA monoclonal antibodies on paraffin sections, and for relative AgNOR area and number on semithin Epon-Araldite sections [15].
  • Statistical analysis of our data shows that the intensity of the immunohistochemical stain, as reflected in the nuclear scores of p53, is a reliable parameter that can differentiate between LGD and HGD of the oral mucosa [16].

Associations of HGD with chemical compounds

  • Reexamination of all 29 mutations and polymorphisms thus far described in HGO shows that these nucleotide changes are not randomly distributed; the CCC sequence motif and its inverted complement, GGG, are preferentially mutated [8].
  • These analyses also demonstrated that the nucleotide substitutions in HGO do not involve CpG dinucleotides, which illustrates important differences between HGO and other genes for the occurrence of mutation at specific short-sequence motifs [8].
  • Homogentisate 1,2-dioxygenase (HGD) is a mononuclear Fe(II)-dependent oxygenase that catalyzes the third step in the pathway for the catabolism of tyrosine, the conversion of homogentisate (HG) to maleylacetoacetate (MAA) [17].
  • In addition, in SE, LGD, and HGD samples, the pattern of cyclin B1 expression was assessed by determination of the presence of positive cells in four mucosal compartments: the deep glandular zone, the lower crypt zone, the upper crypt zone, and the luminal surface [18].
  • Because of the deficient activity of the enzyme homogentisic acid oxidase, homogentisic acid accumulates in plasma, is deposited in various tissues and is excreted in large amounts in urine [19].

Regulatory relationships of HGD

  • More importantly, although 0 of 6 biopsies with HGD (0%) expressed Glut1, 9 of 13 biopsies with adenocarcinoma (69%) were Glut1 positive (P = 0.0108, Fisher's exact test) [20].

Other interactions of HGD

  • The results show complete cosegregation (Z = 6.32; theta = 0) between a C-->T transition at position 817 of the human HGO cDNA and AKU [10].
  • METHODS: A mutation screen of the entire coding region of the HGO gene was performed using single stranded conformational analysis after polymerase chain reaction with oligonucleotide primers flanking all 14 exons of the HGO gene [13].
  • All hyperplastic components expressed HGM, 5 (22.7%) of which were accompanied by focal intestinal metaplasia demonstrated by MUC2 expression, whereas intestinalization frequently occurred in neoplastic components (93% of LGD, 53% of HGD, and 64% of CA components) [21].
  • E-cad decreases from NM to EGC, although not significantly from LGD to HGD; MMP2 is significantly more expressed only in EGC [22].
  • CONCLUSIONS: Reprimo methylation occurs significantly more frequently in BE, HGD, and EAC than in NE or ESCC, suggesting that this epigenetic alteration is a specialized columnar, cell-specific early event with potential as a biomarker for the early detection of esophageal neoplasia [5].

Analytical, diagnostic and therapeutic context of HGD


  1. The molecular basis of alkaptonuria. Fernández-Cañón, J.M., Granadino, B., Beltrán-Valero de Bernabé, D., Renedo, M., Fernández-Ruiz, E., Peñalva, M.A., Rodríguez de Córdoba, S. Nat. Genet. (1996) [Pubmed]
  2. Mutation and polymorphism analysis of the human homogentisate 1, 2-dioxygenase gene in alkaptonuria patients. Beltrán-Valero de Bernabé, D., Granadino, B., Chiarelli, I., Porfirio, B., Mayatepek, E., Aquaron, R., Moore, M.M., Festen, J.J., Sanmartí, R., Peñalva, M.A., de Córdoba, S.R. Am. J. Hum. Genet. (1998) [Pubmed]
  3. Allelic heterogeneity of alkaptonuria in Central Europe. Müller, C.R., Fregin, A., Srsen, S., Srsnova, K., Halliger-Keller, B., Felbor, U., Seemanova, E., Kress, W. Eur. J. Hum. Genet. (1999) [Pubmed]
  4. Minocycline-induced hyperpigmentation masquerading as alkaptonuria in individuals with joint pain. Suwannarat, P., Phornphutkul, C., Bernardini, I., Turner, M., Gahl, W.A. Arthritis Rheum. (2004) [Pubmed]
  5. Reprimo Methylation Is a Potential Biomarker of Barrett's-Associated Esophageal Neoplastic Progression. Hamilton, J.P., Sato, F., Jin, Z., Greenwald, B.D., Ito, T., Mori, Y., Paun, B.C., Kan, T., Cheng, Y., Wang, S., Yang, J., Abraham, J.M., Meltzer, S.J. Clin. Cancer Res. (2006) [Pubmed]
  6. Adrenergic mechanisms contribute to the late phase of hypoglycemic glucose counterregulation in humans by stimulating lipolysis. Fanelli, C.G., De Feo, P., Porcellati, F., Perriello, G., Torlone, E., Santeusanio, F., Brunetti, P., Bolli, G.B. J. Clin. Invest. (1992) [Pubmed]
  7. Crystal structure of human homogentisate dioxygenase. Titus, G.P., Mueller, H.A., Burgner, J., Rodríguez De Córdoba, S., Peñalva, M.A., Timm, D.E. Nat. Struct. Biol. (2000) [Pubmed]
  8. Analysis of alkaptonuria (AKU) mutations and polymorphisms reveals that the CCC sequence motif is a mutational hot spot in the homogentisate 1,2 dioxygenase gene (HGO). Beltrán-Valero de Bernabé, D., Jimenez, F.J., Aquaron, R., Rodríguez de Córdoba, S. Am. J. Hum. Genet. (1999) [Pubmed]
  9. The human homogentisate 1,2-dioxygenase (HGO) gene. Granadino, B., Beltrán-Valero de Bernabé, D., Fernández-Cañón, J.M., Peñalva, M.A., Rodríguez de Córdoba, S. Genomics (1997) [Pubmed]
  10. Molecular diagnosis of alkaptonuria mutation by analysis of homogentisate 1,2 dioxygenase mRNA from urine and blood. Ramos, S.M., Hernández, M., Roces, A., Larruga, J.M., González, P., González, A.M., Pinto, F.M., Cabrera, V.M. Am. J. Med. Genet. (1998) [Pubmed]
  11. Molecular basis of a progressive juvenile-onset hereditary cataract. Pande, A., Pande, J., Asherie, N., Lomakin, A., Ogun, O., King, J.A., Lubsen, N.H., Walton, D., Benedek, G.B. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  12. Aortic stenosis in cardiovascular ochronosis. Ffolkes, L.V., Brull, D., Krywawych, S., Hayward, M., Hughes, S.E. J. Clin. Pathol. (2007) [Pubmed]
  13. Ocular ochronosis in alkaptonuria patients carrying mutations in the homogentisate 1,2-dioxygenase gene. Felbor, U., Mutsch, Y., Grehn, F., Müller, C.R., Kress, W. The British journal of ophthalmology. (1999) [Pubmed]
  14. Up-regulation of cyclooxygenase-2 in squamous carcinogenesis of the esophagus. Shamma, A., Yamamoto, H., Doki, Y., Okami, J., Kondo, M., Fujiwara, Y., Yano, M., Inoue, M., Matsuura, N., Shiozaki, H., Monden, M. Clin. Cancer Res. (2000) [Pubmed]
  15. Cell proliferation patterns and p53 expression in gastric dysplasia. Miracco, C., Spina, D., Vindigni, C., Filipe, M.I., Tosi, P. Int. J. Cancer (1995) [Pubmed]
  16. Image analysis of p53 and cyclin D1 expression in premalignant lesions of the oral mucosa. Liu, S.C., Hu, Y., Sauter, E.R., Clapper, M.L., Chen, S.Y., Lanfranchi, H.E., Engstrom, P.F., Klein-Szanto, A.J. Anal. Quant. Cytol. Histol. (1999) [Pubmed]
  17. Kinetic analysis of human homogentisate 1,2-dioxygenase. Amaya, A.A., Brzezinski, K.T., Farrington, N., Moran, G.R. Arch. Biochem. Biophys. (2004) [Pubmed]
  18. Expression of cyclin B1 in the metaplasia-dysplasia-carcinoma sequence of Barrett esophagus. Geddert, H., Heep, H.J., Gabbert, H.E., Sarbia, M. Cancer (2002) [Pubmed]
  19. Alkaptonuric ochronosis: report of two affected brothers. Gutzmer, R., Herbst, R.A., Kiehl, P., Kapp, A., Weiss, J. J. Am. Acad. Dermatol. (1997) [Pubmed]
  20. Human erythrocyte glucose transporter (Glut1) is immunohistochemically detected as a late event during malignant progression in Barrett's metaplasia. Younes, M., Ertan, A., Lechago, L.V., Somoano, J., Lechago, J. Cancer Epidemiol. Biomarkers Prev. (1997) [Pubmed]
  21. Malignant transformation of gastric hyperplastic polyps: alteration of phenotypes, proliferative activity, and p53 expression. Yao, T., Kajiwara, M., Kuroiwa, S., Iwashita, A., Oya, M., Kabashima, A., Tsuneyoshi, M. Hum. Pathol. (2002) [Pubmed]
  22. Cell proliferation, cell death, E-cadherin, metalloproteinase expression and angiogenesis in gastric cancer precursors and early cancer of the intestinal type. Spina, D., Vindigni, C., Presenti, L., Schürfeld, K., Stumpo, M., Tosi, P. Int. J. Oncol. (2001) [Pubmed]
  23. Cloning of the homogentisate 1,2-dioxygenase gene, the key enzyme of alkaptonuria in mouse. Schmidt, S.R., Gehrig, A., Koehler, M.R., Schmid, M., Müller, C.R., Kress, W. Mamm. Genome (1997) [Pubmed]
  24. Barrett's esophagus: surveillance and treatment. Katzka, D.A. Gastroenterol. Clin. North Am. (2002) [Pubmed]
  25. Optimization of light dosimetry for photodynamic therapy of Barrett's esophagus: efficacy vs. incidence of stricture after treatment. Panjehpour, M., Overholt, B.F., Phan, M.N., Haydek, J.M. Gastrointest. Endosc. (2005) [Pubmed]
  26. Poor results of 5-aminolevulinic acid-photodynamic therapy for residual high-grade dysplasia and early cancer in barrett esophagus after endoscopic resection. Peters, F., Kara, M., Rosmolen, W., Aalders, M., Ten Kate, F., Krishnadath, K., van Lanschot, J., Fockens, P., Bergman, J. Endoscopy. (2005) [Pubmed]
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