THE MOLECULAR-BASIS OF ALKAPTONURIA

Alkaptonuria (AKU) occupies a unique place in the history of human gen etics because it was the first disease to be interpreted as a mendelia n recessive trait by Garrod in 1902. Alkaptonuria is a rare metabolic disorder resulting from loss of homogentisate 1,2 dioxygenase (HGO) ac tivity. Affected individuals accumulate large quantities of homogentis ic acid, an intermediary product of the catabolism of tyrosine and phe nylalanine, which darkens the urine and deposits in connective tissues causing a debilitating arthritis. Here we report the cloning of the h uman 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 harbo urs 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.