Molecular basis of Alkaptonuria and other metabolic disorders.

Alkaptonuria (AKU) is a recessive autosomic trait with medical and historic interest because AKU was the first disease interpreted by Mendel´s theories (Garrod, 1902). In 1996, we cloned the HGO gene and demonstrated that it was the gene responsible for the alcaptonuria disease identifying two families where patients were homozygous or heterozygous for loss-of-function mutations. Later on, we identified several novel mutations in patients from many different countries and characterized them functionally. These were followed by the analysis of the biochemical aspects of the protein encoded by the AKU gen and determination of the crystal structure of the HGO enzyme. All this provided us with the context to analyse the structural bases of the AKU mutations. We also performed genetic epidemiology studies and analyzed the reasons for the increased frequencies of AKU in Central Europe and the Dominican Republic. Other studies related with metabolic disorders include the molecular cloning of the genes responsible for the 3-metylcrotonylglycinuria and subsequent functional and epidemiological studies.