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Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis
J M de Vree1, E Jacquemin, E Sturm
1Department of Gastroenterology and Liver Diseases, Academic Medical Center F-0-116, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
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 gamma-glutamyltransferase (gamma-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 gamma-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 gamma-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.
Insights
Mutations in the human MDR3 gene cause progressive familial intrahepatic cholestasis. This liver disease, marked by high gamma-glutamyltransferase (gamma-GT), mirrors a condition seen in mice lacking the mdr2 gene, impacting phospholipid transport.
Area of Science:
- Hepatology
- Genetics
- Molecular Biology
Background:
- Class III multidrug resistance (MDR) P-glycoproteins (P-gp), specifically mdr2 in mice and MDR3 in humans, are crucial for phosphatidylcholine translocation across the hepatocyte canalicular membrane.
- Mice with a disrupted mdr2 gene exhibit a complete absence of biliary phospholipid excretion, leading to progressive liver disease with portal inflammation, bile duct proliferation, and fibrosis.
- This phenotype closely resembles a subtype of progressive familial intrahepatic cholestasis characterized by elevated serum gamma-glutamyltransferase (gamma-GT) activity.
Purpose of the Study:
- To investigate the role of the human MDR3 gene in progressive familial intrahepatic cholestasis with high serum gamma-GT.
- To identify genetic mutations in MDR3 in patients with this specific liver condition.
Main Methods:
- Immunohistochemistry for MDR3 P-gp on liver tissue.
- Reverse transcription-coupled PCR sequence analysis of MDR3.
- Genomic DNA analysis of the MDR3 gene.
Main Results:
- Liver tissue from both patients showed negative canalicular staining for MDR3 P-gp.
- Patient 1 had a homozygous 7-bp deletion in MDR3, causing a frameshift and premature stop codon.
- Patient 2 was homozygous for a nonsense mutation in MDR3, resulting in a stop codon.
Conclusions:
- Mutations in the human MDR3 gene are a cause of progressive familial intrahepatic cholestasis with high serum gamma-GT.
- The histopathological findings in these patients are consistent with the mdr2(-/-) mouse model, highlighting the conserved role of P-gp in biliary phospholipid excretion.