title: Hereditary Renal Hypouricemia Type 1 and Autosomal Dominant Polycystic Kidney Disease.
abstract: BACKGROUND
  Renal hypouricemia (RHUC) is a heterogeneous inherited disorder characterized by impaired tubular uric acid (UA) transport with severe complications, such as acute kidney injury. Type 1 is caused by a mutation in the SLC22A12 gene (URAT1) and type 2 in the SLC2A9 gene (GLUT9). In this article, the authors present a coexpression functional characterization of variants responsible for RHUC type 1 in a Czech family with polycystic kidney disease (PKD).
  
  
  METHODS
  The serum UA concentration in the proband was 1.1 mg/dL and was expressed as an increase in the fractional excretion of UA (43%). The URAT1 allelic variants were prepared and their urate uptake and subcellular localization were studied by Xenopus oocytes expression system. Linkage analysis using a panel of 4 CA-repeat flanking markers for chromosome 16 and a panel of 3 CA-repeat flanking markers for chromosome 4 was performed, which carry the PKD1 and PKD2 genes, respectively.
  
  
  RESULTS
  Coexpression results showed that p.G366R and p.R477H suppressed urate transport by wild types. Colocalization studies showed an accumulation of URAT1 in the endoplasmic reticulum of the p.G366R variant and mainly retention of wild-type protein by variants p.G366R and p.R477H.
  
  
  CONCLUSIONS
  The findings suggest that not only loss-of-function mutation of URAT1 but also the dominant-negative effect cause RHUC through loss of UA absorption, partly due to protein misfolding caused by accumulation of URAT1 protein in the endoplasmic reticulum.
authors.affiliation: Institute of Rheumatology (BS), Prague, Czech Republic; Institute of Inherited Metabolic Disorders (BS), First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Czech Republic; Institute of Biology and Medical Genetics (JS), First Faculty of Medicine, Charles University, Prague and General University Hospital, Czech Republic; Department of Pathophysiology (MN), Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan; and Division of Kidney and Hypertension (MN, KI), Jikei University School of Medicine, Tokyo, Japan.
authors.forename: Blanka
authors.initials: B
authors.lastname: Stiburkova
authors.forename: Jitka
authors.initials: J
authors.lastname: Stekrova
authors.forename: Makiko
authors.initials: M
authors.lastname: Nakamura
authors.forename: Kimiyoshi
authors.initials: K
authors.lastname: Ichida
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D000818:Animals; D018153:Czech Republic; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D008040:Genetic Linkage; D051246:Glucose Transport Proteins, Facilitative / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D008297:Male; D009154:Mutation; D009865:Oocytes; D027361:Organic Anion Transporters / Q000235:genetics; D027701:Organic Cation Transport Proteins / Q000235:genetics; D016891:Polycystic Kidney, Autosomal Dominant / Q000150:complications* / Q000235:genetics*; D017510:Protein Folding; D015499:Renal Tubular Transport, Inborn Errors / Q000150:complications* / Q000235:genetics*; D014527:Uric Acid / Q000097:blood; D014545:Urinary Calculi / Q000150:complications* / Q000235:genetics*; D014982:Xenopus laevis
chemical_list: D051246:Glucose Transport Proteins, Facilitative; D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins; C491241:SLC22A12 protein, human; C411811:SLC2A9 protein, human; D014527:Uric Acid