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The molecular basis of alkaptonuria


Alkaptonuria (AKU) occupies a unique place in the history of human genetics because it was the first disease to be interpreted as a mendelian recessive trait by Garrod in 1902. Alkaptonuria is a rare metabolic disorder resulting from loss of homogentisate 1,2 dioxygenase (HGO) activity. Affected individuals accumulate large quantities of homogentisic acid, an intermediary product of the catabolism of tyrosine and phenylalanine, which darkens the urine and deposits in connective tissues causing a debilitating arthritis. Here we report the cloning of the human HGO gene and establish that it is the AKU gene. 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.

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  1. O'Brien, W.M., La Du, B.N. & Bunim, J.J. Biochemical, pathological and clinical aspects of alkaptonuria, ochronosis and ochronotic arthropaty: Review of world literature (1584–1962). Am. J. Med. 34, 813–838 (1963).

    Google Scholar 

  2. La Du, B.N., Zannoni, V.G., Laster, L. & Seegmiller, J.E. The nature of the defect in tyrosine metabolism in alcaptonuria. J. Biol. Chem. 230, 251–260 (1958).

    CAS  PubMed  Google Scholar 

  3. Garrod, A.E. The incidence of alkaptonuria: a study in clinical individuality. Lancet 2, 1616–1620 (1902).

    Google Scholar 

  4. Garrod, A.E., The Croonian Lectures on inborn errors of metabolism Lecture II. Alkaptonuria. Lancef 2, 73–79 (1908).

    Google Scholar 

  5. Pollak, M.R. et al. Homozygosity mapping of the gene for alkaptonuria to chromosome 3q2. Nature Genet. 5, 201–204 (1993).

    Article  CAS  Google Scholar 

  6. Janocha, J. et al. The human gene for alkaptonuria (AKU) maps to chromosome 3q. Genomics 19, 5–8 (1994).

    Article  CAS  Google Scholar 

  7. Montagutelli, X. et al. aku, a mutation of the mouse homologous to human alkaptonuria maps to chromosome 16. Genomics 19, 9–11 (1994).

    Article  CAS  Google Scholar 

  8. Schmidt, S.R., Müller, C.R. & Kress, W. Murine liver homogentisate 1,2-dioxygenase. Purification to homogeneity and novel biochemical properties. Eur. J. Biochem. 228, 425–430 (1995).

    Article  CAS  Google Scholar 

  9. Fernández-Cañón, J.M. & Peñalva, M. A. Fungal metabolic model for human type I hereditary tyrosinaemia. Proc. Natl. Acad. Sci. USA 92, 9132–9136 (1995).

    Article  Google Scholar 

  10. Fernández-Cañón, J.M. & Peñalva, M. A. Molecular characterization of a gene encoding a homogentisate dioxygenase from Aspergillus idulans and identification of its human and plant homologues. J. Biol. Chem. 270, 21199–21205 (1995).

    Article  Google Scholar 

  11. Zannoni, V.G., Seegmiller, J.E. & La Du, B. N. Nature of the defect in alkaptonuria. Nature 193, 952–953 (1962).

    Article  CAS  Google Scholar 

  12. Srsen, S. Akaptonuria (Osveta Publishers, Martin [in Slovak], (1984).

  13. Srsen, S., Srsnova, K. & Lanyi, A. Clinical manifestation of alkaptonuria in relation to age [in Slovak]. Bratis. Lek. Listy 77, 662–669 (1982).

    CAS  Google Scholar 

  14. Srsen, S., Vondracek, J., Srsnova, K. & Svac, J. Analysis of the life span of alkaptonuric patients [in Slovak]. Cas. Lek. Ces. 124, 1288–1291 (1985).

    CAS  Google Scholar 

  15. Zannoni, V.G., Lomtevas, N. & Goldfinger, S. Oxidation of homogentisic acid to ochronotic pigment in connective tissue. Biochim. Biophys. Acta 177, 94–105 (1969).

    Article  CAS  Google Scholar 

  16. Wolf, J.A. et al. Effects of ascorbic acid in alkaptonuria: alterations in benzoquinone acetic acid and an ontogenic effect in infancy. Pediatr. Res. 26, 140–144 (1989).

    Article  Google Scholar 

  17. Levine, M. New concepts in the biology and biochemistry of ascorbic acid. N. Engl. J. Med. 314, 892–902 (1986).

    Article  CAS  Google Scholar 

  18. Kamoun, P., Coudé, M., Forest, M., Montagutelli, X. & Guénet, J. L. Ascorbic acid and alkaptonuria. Eur. J. Pediatr. 151, 149 (1992).

    Article  CAS  Google Scholar 

  19. Roth, M. & Felgenhauer, W. R. Recherche de I'excrétion d'acide homogentisique urinarie chez des hétérozygotes pour I'alcaptonurie. Enzym. Biol. Clin. 9, 53–58 (1968).

    Article  CAS  Google Scholar 

  20. Fernández-Ruiz, E. et al. Mapping of the human VLA-a4 gene to chromosome 2q31-q32. Eur.J.Immunol. 22, 587–590 (1992).

    Article  Google Scholar 

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Fernández-Cañón, J., Granadino, B., De Bernabé, D. et al. The molecular basis of alkaptonuria. Nat Genet 14, 19–24 (1996).

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