title: Mutation and functional analysis of ABCC2/multidrug resistance protein 2 in a Japanese patient with Dubin-Johnson syndrome.
abstract: 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.
authors.affiliation: Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Uchiumi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tanamachi
authors.forename: Kajiyo
authors.initials: K
authors.lastname: Kuchiwaki
authors.forename: Mitsuharu
authors.initials: M
authors.lastname: Kajita
authors.forename: Shinya
authors.initials: S
authors.lastname: Matsumoto
authors.forename: Mikako
authors.initials: M
authors.lastname: Yagi
authors.forename: Tomotake
authors.initials: T
authors.lastname: Kanki
authors.forename: Dongchon
authors.initials: D
authors.lastname: Kang