Disruption of HNF1α binding site causes inherited severe unconjugated hyperbilirubinemia
| Autor: | Vincent A. van der Mark, Isabel Mayayo-Peralta, Piter J. Bosma, Ulrich Beuers, Sem J. Aronson, Nevin Oruc, Rob J. de Knegt, Remco van Dijk, Anja A. Kattentidt-Mouravieva |
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| Přispěvatelé: | Graduate School, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Obstetrics & Gynecology, Gastroenterology & Hepatology |
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Adult
medicine.medical_specialty Transcription Genetic Crigler–Najjar syndrome Molecular Sequence Data Glucuronidation Receptors Cytoplasmic and Nuclear Biology medicine.disease_cause digestive system Internal medicine Constitutive androstane receptor medicine Humans Hepatocyte Nuclear Factor 1-alpha Glucuronosyltransferase Binding site Promoter Regions Genetic Constitutive Androstane Receptor Crigler-Najjar Syndrome Unconjugated hyperbilirubinemia Mutation Binding Sites Base Sequence Hepatology Homozygote Sequence Analysis DNA medicine.disease Mutagenesis Insertional Endocrinology Liver Nuclear receptor Female Phenobarbital medicine.drug |
| Zdroj: | Journal of hepatology, 63(6), 1525-1529. Elsevier Journal of Hepatology, 63(6), 1525-1529. Elsevier |
| ISSN: | 0168-8278 |
| DOI: | 10.1016/j.jhep.2015.07.027 |
| Popis: | Crigler-Najjar syndrome presents as severe unconjugated hyper-bilirubinemia 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 HNF1 alpha 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 HNF1 alpha 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. (C) 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. |
| Databáze: | OpenAIRE |
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