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Mutation and functional analysis of ABCC 2/multidrug resistance protein 2 in a J apanese patient with D ubin– J ohnson syndrome
Author(s) -
Uchiumi Takeshi,
Tanamachi Hiroyuki,
Kuchiwaki Kajiyo,
Kajita Mitsuharu,
Matsumoto Shinya,
Yagi Mikako,
Kanki Tomotake,
Kang Dongchon
Publication year - 2013
Publication title -
hepatology research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.123
H-Index - 75
eISSN - 1872-034X
pISSN - 1386-6346
DOI - 10.1111/j.1872-034x.2012.01103.x
Subject(s) - hek 293 cells , mutation , missense mutation , microbiology and biotechnology , exon , transfection , endoplasmic reticulum , nonsense mutation , compound heterozygosity , gene , chemistry , biology , genetics
D ubin– J ohnson 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 ( ABCC 2/ MRP 2) on the canalicular membrane of hepatocytes. We performed mutational analysis of the ABCC 2 / MRP 2 gene in a J apanese female with DJS . Furthermore, we investigated the effects of the two identified DJS ‐associated mutations on MRP 2 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 ABCC 2/ MRP 2. We established HEK 293 cell lines stably expressing one of the two identified DJS ‐associated mutations. Expressed W709R MRP 2 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 MRP 2 protein was expressed from HEK 293 cells transfected with an R1310X ‐containing construct. This compound heterozygous mutation of the MRP 2 gene causes dysfunction of the MRP 2 protein and the hyperbilirubinemia seen in DJS .