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. José M. Fernández-Cañón and Begoña Granadino: J.M.F.-C. & B.G. contributed equally to this work.


  1. Departamento de Microbiología Molecular, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Veláuez 144, 28006, Madrid, Spain

    • José M. Fernández-Cañón
    •  & Miguel A. Peñalva
  2. Departamento de Inmunología, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Veláuez 144, 28006, Madrid, Spain

    • Begoña Granadino
    • , Daniel Beltrán–Valero De Bernabé
    •  & Santiago Rodríguez De Córdoba
  3. Unidad de Biología Molecular, Hospital de la Princesa, Universidad Autínoma de Madrid, 28006, Madrid, Spain

    • Mónica Renedo
    •  & Elena Fernández-Ruiz


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