Genetic diseases

Ivan Sebesta 1 5 9 15 16 22 32 41 49 54 Blanka Stiburkova 0 4 8 14 16 21 31 40 48 53 Kimiyoshi Ichida 3 7 13 16 20 30 39 47 52 Makoto Hosoyamada 2 6 12 11 16 27 36 45 51 55 0 Cnr Ibim and Ospedali Riuniti , Reggio Cal. 1 Cnr-Ibim, Reggio Calabria 2 Division of Pharmacotherapeutics, Faculty of Pharmacy, Keio University , Tokyo, Japan 3 Saarland University Medical Center 4 Clinical Chemistry and Laboratory Medicine/Central Laboratory, Saarland University Medical Center , Homburg, Germany 5 Department of Internal Medicine IV, Saarland University Medical Center , Homburg, Germany 6 Department of Nephrology, Hippokrateon Hospital , Nicosia, Cyprus 7 Medical University Graz, Clinical Institute of Medical and Chemical Laboratory Diagnostics , Graz, Austria 8 Medical University Vienna, Department of Medicine III, Division of Nephrology & Dialysis 9 Medical University Vienna, Department of Medicine III, Division of Nephrology & Dialysis , Vienna, Austria 10 Medical University Graz, Department of Pediatrics , Graz, Austria 11 Renal Research Institute , New York USA 12 Department of Internal Medicine IV, Section of Nephrology , Klinikum Wels-Grieskirchen, Wels, Austria 13 Academic Teaching Hospital Feldkirch 14 Academic Endocrine Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism (Ocdem), Churchill Hospital, University of Oxford , Headington, Oxford, UK 15 Renal Research Institute , New York, New York, USA 16 of Neurology, Children's Hospital and Research Center Oakland , Oakland, Ca 17 Department of Pediatrics and Neurology, Cincinnati Children's Hospital Medical Center , Cincinnati, Oh, USA 18 Division of Pediatric Neurology, Mattel Children's Hospital at Ucla , Los Angeles, Ca, USA 19 Novartis Pharmaceuticals Corporation , Florham Park, Nj, USA 20 Minnesota Epilepsy Group, St. Paul, Mn, USA 21 Novartis Pharmaceuticals Corporation , East Hanover, Nj, USA 22 University Medical Center Utrect , Utrecht, The Netherlands 23 Texas Scottish Rite Hospital for Children , Dallas, TX, USA 24 Department of Genetics, University of Alabama at Birmingham , Birmingham, Al, USA 25 Department of Neurology, University of Alabama School of Medicine , Birmingham, Al, USA 26 Charite-Universittsmedizin Berlin , Berlin, Germany 27 Royal Sussex County Hospital , Brighton, UK 28 University of Chicago and Comer Children's Hospital , Chicago, Il, USA 29 Children's Healthcare of Atlanta , Atlanta, Ga, USA 30 Department of Immunology, Genetics and Pathology, Uppsala University , Uppsala, Sweden 31 Department of Biomedicine, Aarhus University , Aarhus, Denmark 32 Institute for Biomedicine, Aarhus University , Aarhus, Denmark 33 Pathology Unit, Karolinska University Hospital, Karolinska Institute , Stockholm, Sweden 34 Department of Women's and Children's Health, Uppsala University , Uppsala, Sweden 35 Department of Biomedicine, Aarhus University 36 Department of Audiology, Bispebjerg Hospital and Wilhelm Johannsen Centre of Functional Genomics, Institute of Cellular and Molecular Medicine, University of Copenhagen, The Panum Institute , Copenhage 37 Department of Neuroscience, Uppsala University , Uppsala, Sweden 38 Department of Clinical Genetics, Odense University Hospital , Odense, Denmark 39 Ist Department of Pediatrics, Semmelweis University , Budapest, Hungary 40 First Department of Pediatrics, Semmelweis University 41 First Department of Pediatrics, Semmelweis University , Budapest, Hungary 42 University of Pcs , Hungary 43 Departments of Pediatrics and Human Genetics, University of Michigan , Ann Arbor, Michigan, USA 44 Inserm U983, Hpital Necker, Paris, France 45 Szent Jnos Hospital , Budapest, Hungary 46 University of Debrecen , Hungary 47 Department of Nephrology, Transplantology and Internal Medicine , Gdansk, Poland 48 Center for Nephrology and Metabolic Disorders , Weisswasser, Germany 49 1department of Endocrinology and Internal Medicine, Medical University of Gdansk , Poland 50 Department of Nephrology, Transplantology and Internal Medicine, Medical University of Gdansk 51 Department of Endocrinology and Internal Medicine, Medical University of Gdansk , Poland 52 Service de Nphrologie, Centre Hospitalier de Valenciennes 53 Cliniques Universitaires St Luc, Universit Catholique de Louvain 54 Service de Nphrologie, Cliniques Universitaires St Luc , Bruxelles 55 Service de Gntique, Cliniques Universitaires St Luc , Bruxelles unexplained hypouricemia and urolithiasis was referred to our institute for the purine metabolic investigation. Previous ultrasound investigation revealed renal calculi of 5-6 millimeters in size on the right side when he was that at the age of two months. Very small calculi was found also in the lower part of the right kidney. Results: We have found repeated hypouricemia (53-108 mol/l) and increased fractional excretion of uric acid (24.5-84.2 %) using our diagnostic approach to unexplained hypouricemia. The urinary concentrations of hypoxanhine and xanhine were within normal limits, thus the possible genetic defect of xanthinoxidase was excluded in this Czech patient. No other secondary causes of hyperuricosuric hypouricemia such as Fanconi syndrome, Wilson disease or drug-induced tubulopathy were found. Subsequent mutational analysis revealed novel heterozygous 9bp deletion (1242-1250delGCTGGCAGG) in hURAT1 transporter. Conclusions: Our finding shows that this disorder is present also in Caucasian population. This genetic defect belongs to differential diagnosis of the causes of nephrolithiasis. Patients with unexplained hypouricemia need detailed purine metabolic investigations. (supported by grant VZMSM0021620806, Czech Republic) - MUTATIONAL ANALYSIS OF THE URATE TRANSPORTER 1 GENE IN JAPANESE PATIENTS WITH RENAL HYPOURICEMIA Introduction and Aims: Hypouricemia, defined as low levels of serum urate (less than 2.0 mg/dl), is common in the general population (0.5%-4%). Although the majority of cases with idiopathic renal hypouricemia have been reported in Japanese, it is a rare disorder with an incidence of 0.15% in Japan. Patients with idiopathic renal hypouricemia were found to have defects in a gene (SLC22A12) encoding for human urate transporter 1 (hURAT1). We report Japanese patients with renal hypouricemia. Methods: 1. Five probands with idiopathic renal hypouricemia were investigated. Genomic DNA was extracted from peripheral blood cells. All exons and exon-intron boundaries of hURAT1 gene were analysed by polymerase chain reaction (PCR) and direct sequencing. 2. The rapid method for detecting mutation by PCR-restriction fragment length polymorphism (PCR-RFLP) was developed. 3. Functional analysis of hURAT1 mutant was examined. Results: 1. The serum urate levels in probands were between 0.5 and 1.2 mg/dl. 2. Urolithiasis and exerciseinduced acute renal failure are relatively common complications in renal hypouricemia. However, most patients in this study were clinically unrecognizable. 3. We found five mutations in hURAT1 gene, which were W (...truncated)