title: The molecular basis of alkaptonuria.
abstract: 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.
authors.affiliation: Departmento de Microbiologia Molecular, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Cientificas, Madrid, Spain.
authors.forename: J M
authors.initials: JM
authors.lastname: Fernández-Cañón
authors.forename: B
authors.initials: B
authors.lastname: Granadino
authors.forename: D
authors.initials: D
authors.lastname: Beltrán-Valero de Bernabé
authors.forename: M
authors.initials: M
authors.lastname: Renedo
authors.forename: E
authors.initials: E
authors.lastname: Fernández-Ruiz
authors.forename: M A
authors.initials: MA
authors.lastname: Peñalva
authors.forename: S
authors.initials: S
authors.lastname: Rodríguez de Córdoba
mesh_terms: D000474:Alkaptonuria / Q000235:genetics*; D000595:Amino Acid Sequence; D001483:Base Sequence; D002874:Chromosome Mapping; D002893:Chromosomes, Human, Pair 3; D003001:Cloning, Molecular; D018076:DNA, Complementary; D049308:Dioxygenases; D005260:Female; D050560:Homogentisate 1,2-Dioxygenase; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D010105:Oxygenases / Q000235:genetics* / Q000378:metabolism; D017354:Point Mutation; D011392:Proline / Q000235:genetics; D012694:Serine / Q000235:genetics; D014018:Tissue Distribution
chemical_list: D018076:DNA, Complementary; D012694:Serine; D011392:Proline; D010105:Oxygenases; D049308:Dioxygenases; D050560:Homogentisate 1,2-Dioxygenase