Mutation and functional analysis of ABCC2/multidrug resistance protein 2 in a Japanese patient with Dubin–Johnson syndrome

Dubin–Johnson syndrome (DJS) is a recessive inherited disorder characterized by conjugated hyperbilirubinemia. It is caused by dysfunction of adenosine triphosphate‐binding cassette, sub‐family C, member 2 (ABCC2/MRP2) on the canalicular membrane of hepatocytes. We performed mutational analysis of the ABCC2/MRP2 gene in a Japanese female with DJS. Furthermore, we investigated the effects of the two identified DJS‐associated mutations on MRP2 function. We found a compound heterozygous mutation in the patient: W709R (c.2124T>C), a missense mutation in exon 17, and R1310X (c.3928C>T), a nonsense mutation in exon 28. DJS‐associated mutations have been shown to impair the protein maturation and transport activity of ABCC2/MRP2. We established HEK293 cell lines stably expressing one of the two identified DJS‐associated mutations. Expressed W709R MRP2 was mainly core‐glycosylated, predominantly retained in the endoplasmic reticulum, and exhibited no transport activity, suggesting that this mutation causes deficient maturation and impaired protein sorting. No MRP2 protein was expressed from HEK293 cells transfected with an R1310X‐containing construct. This compound heterozygous mutation of the MRP2 gene causes dysfunction of the MRP2 protein and the hyperbilirubinemia seen in DJS.     

Hepatobiliary & Pancreatic Diseases International

<正>Copyright 2015,HepatobiliaryPancreatic Diseases International.All rights reserved.www.hbpdint.comGeneral information HepatobiliaryPancreatic Diseases International is a journal published bimonthly in English language by the First Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou,China.We welcome original research articles,review articles,editorials,and others from any part of     

Hepatobiliary & Pancreatic Diseases International

<正>Copyright 2015,HepatobiliaryPancreatic Diseases International.All rights reserved.www.hbpdint.comGeneral information HepatobiliaryPancreatic Diseases International is a journal published bimonthly in the English language by the First Affiliated Hospital,Zhejiang University School of Medi-