Congenital Jaundice in Rats with a Mutation in a Multidrug Resistance-Associated Protein Gene
Science · 1996 · 830 citations · 29 references
GeneticsPathologyMolecular BiologyDisease Gene IdentificationDrug ResistanceBiochemical GeneticsHealth SciencesCongenital JaundiceBiochemistryCanalicular MembraneLiver PhysiologyInherited Metabolic DiseaseProtein TransportCell BiologySignal TransductionGenetic DisorderPathogenesisMedicineHuman Dubin-johnson SyndromeRat Cmoat
The TR(-) rat, an animal model of Dubin‑Johnson syndrome, shows chronic conjugated hyperbilirubinemia due to a defect in the canalicular multispecific organic anion transporter (cMOAT) that normally excretes organic anions from hepatocytes. The rat cmoat gene, homologous to human MRP1, was cloned and shown to encode a canalicular membrane protein expressed in hepatocytes. A single‑nucleotide deletion in cmoat reduces its mRNA and eliminates the protein, likely causing the TR(-) phenotype.
The human Dubin-Johnson syndrome and its animal model, the TR(-) rat, are characterized by a chronic conjugated hyperbilirubinemia. TR(-) rats are defective in the canalicular multispecific organic anion transporter (cMOAT), which mediates hepatobiliary excretion of numerous organic anions. The complementary DNA for rat cmoat, a homolog of the human multidrug resistance gene (hMRP1), was isolated and shown to be expressed in the canalicular membrane of hepatocytes. In the TR(-) rat, a single-nucleotide deletion in this gene resulted in a reduced messenger RNA level and absence of the protein. It is likely that this mutation accounts for the TR(-) phenotype.
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