title: Dual hereditary jaundice: simultaneous occurrence of mutations causing Gilbert's and Dubin-Johnson syndrome.
abstract: OBJECTIVE
  Dubin-Johnson syndrome is recessively inherited, conjugated hyperbilirubinemia induced by mutations in the ABCC2/MRP2 gene encoding the canalicular transporter for conjugated bilirubin. Gilbert's syndrome is recessively inherited, unconjugated hyperbilirubinemia caused by decreased conjugation rate of bilirubin associated mostly with homozygous A(TA) 7 TAA variant of the TATAA-box in the UGT1A1 gene promoter. Our aim was to establish the molecular diagnosis in a 3-year-old male with atypical, intermittent, predominantly unconjugated, hyperbilirubinemia.
  
  
  METHODS
  99m Tc-HIDA cholescintigraphy was used for imaging the biliary tree. Expression of ABCC2/MRP2 protein in hepatocytes was investigated immunohistochemically. UGT1A1 and ABCC2/MRP2 genes were sequenced from genomic DNA, and the mutations were verified by fragment analysis, sequencing the cloned exons, and restriction fragment length polymorphism.
  
  
  RESULTS
  Cholescintigraphy revealed delayed visualization of the gallbladder. A brown granular lipopigment differing from melanin-like pigment reported in Dubin-Johnson syndrome was present in hepatocytes, but, otherwise, liver histology was normal. ABCC2/MRP2 protein was not detected on the canalicular membrane of hepatocytes, and 2 novel mutations were found in the ABCC2/MRP2 gene: a heterozygous in-frame insertion-deletion mutation 1256insCT/delAAACAGTGAACCTGATG in exon 10 inherited from the father and a heterozygous deletion 4292delCA in exon 30 inherited from the mother. In addition, the patient was homozygous for -3279T>G and A(TA) 7 TAA mutations in the UGT1A1 gene promoter.
  
  
  CONCLUSIONS
  Our patient represents a case of digenic mixed hyperbilirubinemia-a distinct type of constitutive jaundice resulting from coinherited defects in ABCC2/MRP2 and UGT1A1 genes.
authors: Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
authors: Dita
authors: D
authors: Cebecauerova
authors: Tomas
authors: T
authors: Jirasek
authors: Lucie
authors: L
authors: Budisova
authors: Vaclav
authors: V
authors: Mandys
authors: Vladimir
authors: V
authors: Volf
authors: Zorka
authors: Z
authors: Novotna
authors: Iva
authors: I
authors: Subhanova
authors: Martin
authors: M
authors: Hrebicek
authors: Milan
authors: M
authors: Elleder
authors: Milan
authors: M
authors: Jirsa
mesh_terms: D002675:Child, Preschool; D005878:Gilbert Disease / Q000150:complications / Q000235:genetics* / Q000473:pathology; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D006933:Hyperbilirubinemia, Hereditary / Q000235:genetics / Q000473:pathology; D007565:Jaundice / Q000235:genetics* / Q000473:pathology; D007566:Jaundice, Chronic Idiopathic / Q000150:complications / Q000235:genetics* / Q000473:pathology; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D000099148:UGT1A1 Enzyme
chemical_list: D014453:Glucuronosyltransferase; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D000099148:UGT1A1 Enzyme; C000715087:ABCC2 protein, human