TY - JOUR
T1 - Disruption of HNF1α binding site causes inherited severe unconjugated hyperbilirubinemia
AU - van Dijk, Remco
AU - Mayayo-Peralta, Isabel
AU - Aronson, Sem J.
AU - Kattentidt-Mouravieva, Anja A.
AU - van der Mark, Vincent A.
AU - de Knegt, Rob
AU - Oruc, Nevin
AU - Beuers, Ulrich
AU - Bosma, Piter J.
PY - 2015
Y1 - 2015
N2 - 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
AB - 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
U2 - https://doi.org/10.1016/j.jhep.2015.07.027
DO - https://doi.org/10.1016/j.jhep.2015.07.027
M3 - Article
C2 - 26220753
SN - 0168-8278
VL - 63
SP - 1525
EP - 1529
JO - Journal of Hepatology
JF - Journal of Hepatology
IS - 6
ER -