title: Disruption of HNF1α binding site causes inherited severe unconjugated hyperbilirubinemia.
abstract: Crigler-Najjar syndrome presents as severe unconjugated hyperbilirubinemia and is characteristically caused by a mutation in the UGT1A1 gene, encoding the enzyme responsible for bilirubin glucuronidation. Here we present a patient with Crigler-Najjar syndrome with a completely normal UGT1A1 coding region. Instead, a homozygous 3 nucleotide insertion in the UGT1A1 promoter was identified that interrupts the HNF1α binding site. This mutation results in almost complete abolishment of UGT1A1 promoter activity and prevents the induction of UGT1A1 expression by the liver nuclear receptors CAR and PXR, explaining the lack of a phenobarbital response in this patient. Although animal studies have revealed the importance of HNF1α for normal liver function, this case provides the first clinical proof that mutations in its binding site indeed result in severe liver pathology stressing the importance of promoter sequence analysis.
authors.affiliation: Department of Gastroenterology and Hepatology and Tytgat Institute for Liver and Intestinal Research, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Remco
authors.initials: R
authors.lastname: van Dijk
authors.affiliation: Department of Gastroenterology and Hepatology and Tytgat Institute for Liver and Intestinal Research, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Isabel
authors.initials: I
authors.lastname: Mayayo-Peralta
authors.affiliation: Department of Gastroenterology and Hepatology and Tytgat Institute for Liver and Intestinal Research, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Sem J
authors.initials: SJ
authors.lastname: Aronson
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: Anja A
authors.initials: AA
authors.lastname: Kattentidt-Mouravieva
authors.affiliation: Department of Gastroenterology and Hepatology and Tytgat Institute for Liver and Intestinal Research, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Vincent A
authors.initials: VA
authors.lastname: van der Mark
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: Rob
authors.initials: R
authors.lastname: de Knegt
authors.affiliation: Department of Gastroenterology and Hepatology, Ege University, Bornova Izmir, Turkey.
authors.forename: Nevin
authors.initials: N
authors.lastname: Oruc
authors.affiliation: Department of Gastroenterology and Hepatology and Tytgat Institute for Liver and Intestinal Research, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Beuers
authors.affiliation: Department of Gastroenterology and Hepatology and Tytgat Institute for Liver and Intestinal Research, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands. Electronic address: p.j.bosma@amc.uva.nl.
authors.forename: Piter J
authors.initials: PJ
authors.lastname: Bosma
mesh_terms: D000328:Adult; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D000090702:Constitutive Androstane Receptor; D003414:Crigler-Najjar Syndrome / Q000145:classification / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D014453:Glucuronosyltransferase / Q000172:deficiency* / Q000235:genetics*; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000378:metabolism*; D006720:Homozygote; D006801:Humans; D008099:Liver / Q000378:metabolism; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D017422:Sequence Analysis, DNA; D014158:Transcription, Genetic / Q000187:drug effects; D000099148:UGT1A1 Enzyme
chemical_list: D000090702:Constitutive Androstane Receptor; D014453:Glucuronosyltransferase; D051538:Hepatocyte Nuclear Factor 1-alpha; D018160:Receptors, Cytoplasmic and Nuclear; D000099148:UGT1A1 Enzyme; C496487:HNF1A protein, human
keywords: Crigler-Najjar syndrome; HNF1α; Promoter mutation; Transcriptional regulation; UGT1A1