TY - JOUR
T1 - Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis
AU - De Vree, J. Marleen L.
AU - Jacquemin, Emmanuel
AU - Sturm, Ekkehard
AU - Cresteil, Danièle
AU - Bosma, Piter J.
AU - Aten, Jan
AU - Deleuze, Jean François
AU - Desrochers, Marc
AU - Burdelski, Martin
AU - Bernard, Olivier
AU - Oude Elferink, Ronald P.J.
AU - Hadchouel, Michelle
PY - 1998/1/6
Y1 - 1998/1/6
N2 - Class HI 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.
AB - Class HI 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.
UR - http://www.scopus.com/inward/record.url?scp=0040284751&partnerID=8YFLogxK
U2 - 10.1073/pnas.95.1.282
DO - 10.1073/pnas.95.1.282
M3 - Article
C2 - 9419367
AN - SCOPUS:0040284751
SN - 0027-8424
VL - 95
SP - 282
EP - 287
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 1
ER -