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Alkaptonuria in Slovakia: thirty-two years of research on phenotype and genotype.

Research on alkaptonuria (AKU; OMIM # 230500) in Slovakia started in 1968 by the Research Laboratory (later on the Institute) for Clinical Genetics at Martin. Its first stage was focused on clinical, biochemical, genetic and epidemiologic questions and on the reasons for the high prevalence of AKU in Slovakia. Based on a screening programme of now over 611,000 inhabitants (509,000 newborns) the world-wide highest incidence of AKU (1 in 19,000) was recorded, and a total of 208 patients (110 children) were registered. Extensive genealogical studies (sometimes over two centuries) resulted in the fusion of several "unrelated" nuclear families into larger pedigrees and enabled tracing most AKU ancestors to their original geographic localities, predominantly in remote mountain areas. A likely founder effect was detected among the shepherd population of the so-called Valachian colonization that resulted in a high degree of inbreeding and persisting genetic isolation. These epidemiologic data formed the basis for molecular studies in collaboration with the Würzburg group. The AKU locus was mapped to human chromosome 3q2 by orthology to the mouse locus aku. Following the cloning of the homogentisate-1,2 dioxygenase (HGD) genes from human and mouse, nine different mutations were identified in 21 AKU index patients. These include 4 missense, 2 splice-site, 2 single-base insertion and 1 deletion mutation. The most frequent mutations among the 42 AKU chromosomes of the index cases are c.648G > A (Gly161Arg; 42.9%), and c.1278insC (Pro370fs; 19.1%). To date, the genotypes of 29 patients and of 74 gene carriers from 21 families have been established. The highest prevalence and allelic heterogeneity were observed in the Kysuce district with five different mutations. Molecular epidemiology studies by haplotyping were carried out to uncover the original geographic localities of all AKU index chromosomes. This strongly suggests that several founders have contributed to the HGD gene mutation pool. While there is no straightforward explanation for the clustering of independent mutations, the genetic isolation in the past is likely to be responsible for the high prevalence of AKU in Slovakia.

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