Alkaptonuria in Italy: polymorphic haplotype background, mutational profile, and description of four novel mutations in the homogentisate 1,2-dioxygenase gene

Editor—Alkaptonuria (AKU, OMIM 203500) is a rare disorder caused by the deficiency of homogentisate 1,2 dioxygenase (HGO, EC 1.13.11.5).1 HGO catalyses the conversion of homogentisate (HGA) to maleylacetoacetate in the phenylalanine/tyrosine catabolic pathway.2 As a consequence, affected subjects excrete HGA in their urine, which becomes dark upon exposure to air. The medical interest in this condition stems from its association with ochronosis, or the deposition of a brownish pigment in connective tissues including cartilage, where its accumulation can produce a debilitating degenerative joint disease.3 AKU occupies a unique place in the history of human genetics because it was the first disorder to be described as a Mendelian recessive trait.4-6 Recent advances in the understanding of the molecular basis of AKU7-9 have verified that loss of function mutations in the HGO gene are responsible for the disease. A few mutations have been repeatedly detected in patients from different European countries. Since these mutations segregated with specific haplotypes, they should be considered to be old mutations that have spread throughout western Europe with migration. However, allelic heterogeneity is the main feature emerging from the above and other studies.7 9-12Most HGO mutations were found in just one family and did not involve CpG dinucleotides. Rather, a preferential occurrence in the CCC sequence motif and its inverted complement GGG has recently been reported.12 Furthermore, some AKU chromosomes escaped mutation detection within the HGO coding region, suggesting the existence of HGO alleles whose defect might be related to gene expression. To determine the extent of allelic heterogeneity in Italian patients, we started a systematic search of AKU families through announcements at relevant National Congresses. We present here the results leading to the identification of four novel mutations. Our data should facilitate future mutation screening …