Nature Genetics
14, 19 - 24 (1996)
doi:10.1038/ng0996-19
The molecular basis of alkaptonuriaJosé M. Fernández-Cañón*, 1, Begoña Granadino*, 2, Daniel Beltrán−Valero De Bernabé2, Mónica Renedo3, Elena Fernández-Ruiz3, Miguel A. Peñalva1, 4
& Santiago Rodríguez De Córdoba2
1Departamento de Microbiología Molecular, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Veláuez 144, 28006-Madrid, Spain
2Departamento de Inmunología, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Veláuez 144, 28006-Madrid, Spain
3Unidad de Biología Molecular, Hospital de la Princesa, Universidad Autínoma de Madrid, 28006-Madrid, Spain
*J.M.F.-C. & B.G. contributed equally to this work.
4e-mail: cibma15@cc.csic.es 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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