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J. Biol. Chem., Vol. 276, Issue 40, 36923-36930, October 5, 2001
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From the Dubin-Johnson syndrome (DJS) is an
inherited disorder characterized by conjugated hyperbilirubinemia and
is caused by a deficiency of the multidrug resistance protein 2 (MRP2)
located in the apical membrane of hepatocytes. The aim of this study
was to identify the mutations in two previously characterized clusters
of patients with Dubin-Johnson syndrome among Iranian and Moroccan Jews
and determine the consequence of the mutations on MRP2 expression and
function by expression studies. All 32 exons and adjacent regions of
the MRP2 gene were screened by polymerase chain reaction and DNA
sequencing. Two novel mutations were identified in exon 25. One
mutation, 3517A
Identification and Functional Analysis of Two Novel Mutations in
the Multidrug Resistance Protein 2 Gene in Israeli Patients with
Dubin-Johnson Syndrome*
§,,,,
Institute of Thrombosis and Hemostasis,
Department of Hematology, Chaim Sheba Medical Center and Sackler
Faculty of Medicine, Tel Aviv University, Tel Hashomer 52621, Israel
and the § Department of Physiology, University of Texas
Southwestern Medical Center, Dallas, Texas 75235
T, predicting a I1173F substitution, was found
in 22 homozygous Iranian Jewish DJS patients from 13 unrelated families
and a second mutation, 3449GA, predicting a R1150H substitution, was
found in 5 homozygous Moroccan Jewish DJS patients from 4 unrelated
families. Use of four intragenic dimorphisms and haplotype analyses
disclosed a specific founder effect for each mutation. The mutations
were introduced into an MRP2 expression vector by site-directed
mutagenesis, transfected into HEK-293 cells, and analyzed by a
fluorescence transport assay, immunoblot, and immunocytochemistry. Continuous measurement of probenecid-sensitive carboxyfluorescein efflux revealed that both mutations impaired the transport activity of
MRP2. Immunoblot analysis and immunocytochemistry showed that MRP2
(R1150H) matured properly and localized at the plasma membrane of
transfected cells. In contrast, expression of MRP2 (I1173F) was low and
mislocated to the endoplasmic reticulum of the transfected cells. These
findings provide an explanation for the DJS phenotype in these two
patient groups. Furthermore, the close localization of the two
mutations identify this region of MRP2 as important for both
activity and processing of the protein.
*
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence may be addressed: Inst. of Thrombosis
and Hemostasis, Dept. of Hematology, Sheba Medical Center, Tel Hashomer
52621, Israel. Tel.: 972-3-5302104; Fax: 972-3-5351568; E-mail: zeligson@post.tau.ac.il.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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