Alkaptonuria in the Dominican Republic: identification of the founder AKU mutation and further evidence of mutation hot spots in the HGO gene.

Alkaptonuria (AKU, MIM 203500), the first human disease to be recognised as a recessive trait and Archibald Garrod’s prototype “inborn error of metabolism”, 2 is a rare disorder of the phenylalanine and tyrosine catabolic pathway caused by the deficiency of homogentisate dioxygenase (HGO, EC 1.13.11.5) activity. AKU patients are homozygous, or compound heterozygous, for loss of function mutations in HGO. As a consequence of this defect, AKU patients cannot convert homogentisate to maleylacetoacetate, which results in homogentisic aciduria, ochronosis, and arthritis. AKU shows remarkable allelic heterogeneity. More than 40 different AKU mutations have been identified in a total of fewer than 100 unrelated patients from many different countries. In addition to the AKU mutations, 19 polymorphisms have been encountered within the human HGO gene (for a complete description of the HGO mutations and polymorphisms see the AKU database (http://www.cib.csic.es/∼akudb/index.htm)). The analysis of the haplotype association of polymorphisms in the AKU chromosomes has been very useful for the identification of the different AKU alleles and for tracing their migration during recent human history. In this regard, it has been shown that the three most widespread AKU mutation in Europe, M368V, V300G, and P230S (representing 20%, 5%, and 5% of European AKU chromosomes, respectively) are not recurrent mutations. Instead they are probably old mutations that were introduced into Europe with the founder populations and have spread throughout western Europe with the different migrations. Analysis of the HGO mutations and polymorphisms has also shown that the GGG sequence motif (or its reverse complement CCC) is a mutational hot spot in the HGO gene. AKU has a very low prevalence (1:100 000-250 000) in most populations. However, in certain areas, such as the Dominican Republic and Slovakia, the incidence of alkaptonuria is unusually high. 9 In Slovakia, AKU has an approximate incidence of 1:19 000 and shows unexpected allelic heterogeneity. As many as 10 different AKU mutations have been identified in AKU Slovak patients, suggesting that several independent founders have contributed to the AKU gene pool in this geographical location. Recently, we provided evidence indicating that the most prevalent Slovak mutations (G152fs, G161R, G270R, and P370fs) most likely originated in Slovakia at a single and very small geographical location, the Kysuce region, in the northern part of the country. Our data also suggested that increased mutation rates in HGO, associated with GGG triplets and other mutational hot spots, were probably involved in the origin of these Slovak mutations. No molecular data are yet available from the Dominican AKU patients. However, early epidemiological data suggest that the high incidence of AKU in the Dominican Republic could be the consequence of a classical founder effect. In these early studies, as many as 47 AKU cases were reported occurring in eight highly inter-related kindreds in a mixed Spanish-Indian group living in rural Santo Domingo. To determine whether the high incidence of AKU in the Dominican Republic is the consequence of a founder effect (as suggested by the epidemiological data) or an increased mutation rate in the HGO gene (as seems to have been the case in Slovakia), we have performed HGO mutation/polymorphism analyses in eight unrelated Dominican AKU patients and their relatives. These patients are all from the same geographical area as the eight kindreds described by Milch in 1960 and we have confirmed that at least one of the Dominican AKU patients included in our study belongs to one of those kindreds. This patient and the common geographical origin allow us to link the present molecular studies with Milch’s epidemiological data.