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Novel mutations in the homogentisate- 1,2-dioxygenase gene identified in Slovak patients with alkaptonuria
  1. A ZATKOVÁ*,
  4. M ZVARÍK,
  5. V BOŠÁK,
  7. J MATUŠEK§,
  8. V FERÁK,
  9. L KÁDASI*
  1. * Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, Vlárska 5, SK 833 34 Bratislava, Slovakia
  2. Department of Molecular Biology, Faculty of Natural Sciences, Comenius University Bratislava, Mlynská dolina, B2, 842 15 Bratislava, Slovakia
  3. Research Institute of Rheumatic Disease, Nábrezie I Krasku 4, 921 01 Pieštany, Slovakia
  4. § Institute of Criminalistics, Sklabinská 1, 812 72 Bratislava, Slovakia
  1. Dr Zatková, zatkova{at}

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Editor—Alkaptonuria (AKU, McKusick No 203500), a rare autosomal recessive disorder (1:250 000),1 is a classical example of a specific biochemical lesion leading to degenerative disease. As a result of deficiency of homogentisic acid 1,2-dioxygenase activity (HGO, E.C., AKU patients are unable to degrade homogentisic acid (HGA), an intermediary metabolite in phenylalanine and tyrosine catabolism.2 Accumulated HGA is excreted into the urine in large amounts, which darkens on standing. Over the years, benzoquinone acetic acid, an oxidation product of HGA, is deposited in connective tissues, causing their pigmentation (ochronosis), which leads to painful and disabling arthropathy of the large joints and spine (ochronotic arthropathy).

AKU was the first disease interpreted in terms of Mendelian inheritance.3 The HGO gene in humans is located on chromosome 3q21-23.1 4 5Fernandez-Canon et al 5 cloned the human HGO gene and by identifying the first loss of function mutations also provided formal proof that AKU results from a defect in this gene. So far, 24 different mutations have been identified in the HGO gene in patients from various populations.5-10

Notable exceptions to the low prevalence of AKU in all ethnic groups studied are the Dominican Republic and Slovakia (1:19 000).11 12 Founder effects as the consequence of genetic isolation have been postulated to explain this observation. Here, we present results of mutation screening of theHGO gene in 32 AKU chromosomes carried by 17 Slovak AKU patients (in two families, one chromosome was shared by two patients from different generations). All 14 exons of theHGO gene were amplified from genomic DNA, using PCR primers and conditions as described by Fernandez-Canonet al. 5 PCR products were analysed for the presence of mutations by non-radioactive single strand conformation polymorphism analysis …

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