NDLI: Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis

Content Provider	PubMed Central
Author	Vree, J. Marleen L. De Jacquemin, Emmanuel Sturm, Ekkehard Cresteil, Danièle Bosma, Piter J. Aten, Jan Deleuze, Jean-françois Desrochers, Marc Martin, Burdelski Bernard, Olivier Elferink, Ronald P. J. Oude Michelle, Hadchouel
Copyright Year	1998
Abstract	Class III multidrug resistance (MDR) P-glycoproteins (P-gp), mdr2 in mice and MDR3 in man, mediate the translocation of phosphatidylcholine across the canalicular membrane of the hepatocyte. Mice with a disrupted mdr2 gene completely lack biliary phospholipid excretion and develop progressive liver disease, characterized histologically by portal inflammation, proliferation of the bile duct epithelium, and fibrosis. This disease phenotype is very similar to a subtype of progressive familial intrahepatic cholestasis, hallmarked by a high serum γ-glutamyltransferase (γ-GT) activity. We report immunohistochemistry for MDR3 P-gp, reverse transcription-coupled PCR sequence analysis, and genomic DNA analysis of MDR3 from two progressive familial intrahepatic cholestasis patients with high serum γ-GT. Canalicular staining for MDR3 P-gp was negative in liver tissue of both patients. Reverse transcription-coupled PCR sequencing of the first patient’s sequence demonstrated a homozygous 7-bp deletion, starting at codon 132, which results in a frameshift and introduces a stop codon 29 codons downstream. The second patient is homozygous for a nonsense mutation in codon 957 (C → T) that introduces a stop codon (TGA). Our results demonstrate that mutations in the human MDR3 gene lead to progressive familial intrahepatic cholestasis with high serum γ-GT. The histopathological picture in these patients is very similar to that in the corresponding mdr2(−/−) mouse, in which mdr2 P-gp deficiency induces complete absence of phospholipid in bile.
Starting Page	282
File Format	PDF
ISSN	10916490
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	1
Volume Number	95
Language	English
Publisher	National Academy of Sciences
Publisher Date	1998-01-06
Access Restriction	Open
Rights Holder	National Academy of Sciences
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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