title: Novel mutations in xanthine dehydrogenase/oxidase cause severe hypouricemia: biochemical and molecular genetic analysis in two Czech families with xanthinuria type I.
abstract: BACKGROUND
  The article describes the clinical, biochemical, enzymological and molecular genetics findings in two patients from two families with xanthinuria type I.
  
  
  METHODS
  Biochemical analysis using high performance liquid chromatography, allopurinol loading test and analysis of xanthine oxidase activity in plasma and of uromodulin excretion in urine were performed. Sequencing analysis of the xanthine dehydrogenase gene and the haplotype and statistical analyses of consanguinity were performed.
  
  
  RESULTS
  Probands showed extremely low concentrations of uric acid, on seven occasions under the limit of detection. The concentration of uric acid in 38-year-old female was 15 μmol/L in serum and 0.04 mmol/L in urine. Excretion of xanthine in urine was 170 mmol/mol creatinine. The concentration of uric acid in 25-year-old male was 0.03 mmol/L in urine. Excretion of xanthine in urine was 141 mmol/mol creatinine. The allopurinol loading test confirmed xanthinuria type I. The xanthine oxidase activities in patients were 0 and 0.4 pmol/h/mL of plasma. We found three nonsense changes: p.P214QfsX4 and unpublished p.R825X and p.R881X.
  
  
  CONCLUSIONS
  We found two nonconsanguineous compound heterozygotes with xanthinuria type I caused by three nonsense changes. The methods used did not confirm consanguinity in the probands, thus there might be an unconfirmed biological relationship or mutational hotspot.
authors.affiliation: Institute of Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic. bstib@lf1.cuni.cz
authors.forename: Blanka
authors.initials: B
authors.lastname: Stiburkova
authors.forename: Jakub
authors.initials: J
authors.lastname: Krijt
authors.forename: Petr
authors.initials: P
authors.lastname: Vyletal
authors.forename: Josef
authors.initials: J
authors.lastname: Bartl
authors.forename: Eva
authors.initials: E
authors.lastname: Gerhatova
authors.forename: Martin
authors.initials: M
authors.lastname: Korinek
authors.forename: Ivan
authors.initials: I
authors.lastname: Sebesta
mesh_terms: D000328:Adult; D001483:Base Sequence; D015153:Blotting, Western; D018153:Czech Republic; D017931:DNA Primers; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D006239:Haplotypes; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D009154:Mutation; D014527:Uric Acid / Q000097:blood*; D019820:Xanthine / Q000652:urine*; D014968:Xanthine Dehydrogenase / Q000235:genetics*; D014969:Xanthine Oxidase / Q000235:genetics*
chemical_list: D017931:DNA Primers; D019820:Xanthine; D014527:Uric Acid; D014968:Xanthine Dehydrogenase; D014969:Xanthine Oxidase