TY - JOUR
T1 - Genomic structure of the canalicular multispecific organic anion-transporter gene (MRP2/cMOAT) and mutations in the ATP- binding-cassette region in Dubin-Johnson syndrome
AU - Toh, Satoshi
AU - Wada, Morimasa
AU - Uchiumi, Takeshi
AU - Inokuchi, Akihiko
AU - Makino, Yoshinari
AU - Horie, Yutaka
AU - Adachi, Yukihiko
AU - Sakisaka, Shotaro
AU - Kuwano, Michihiko
N1 - Funding Information:
We thank Stephen W. Sherer (The Hospital for Sick Children, Toronto) for fruitful discussions and editorial help, and we also thank Koji Koike and Takanori Nakamura, from our laboratory, for fruitful discussions. This study was supported by grants from the Ministry of Education, Science, Sports, and Culture of Japan; the Fukuoka Anti-Cancer Research Fund; the Second-Term Comprehensive Ten-Year Strategy for Cancer Control, from the Ministry of Health and Welfare; and the CREST (Core Research for Evolutional Science and Technology) of Japan Science and Technology Corporation.
PY - 1999
Y1 - 1999
N2 - Dubin-Johnson syndrome (DJS) is an autosomal recessive disease characterized by conjugated hyperbilirubinemia. Previous studies of the defects in the human canalicular multispecific organic anion transporter gene (MRP2/cMOAT) in patients with DJS have suggested that the gene defects are responsible for DJS. In this study, we determined the exon/intron structure of the human MRP2/cMOAT gene and further characterized mutations in patients with DJS. The human MRP2/cMOAT gene contains 32 exons, and it has a structure that is highly conserved with that of another ATP- binding-cassette gene, that for a multidrug resistance-associated protein. We then identified three mutations, including two novel ones. All mutations identified to date are in the cytoplasmic domain, which includes the two ATP-binding cassettes and the linker region, or adjacent putative transmembrane domain. Our results confirm that MRP2/cMOAT is the gene responsible for DJS. The finding that mutations are concentrated in the first ATP- binding-cassette domain strongly suggests that a disruption of this region is a critical route to loss of function.
AB - Dubin-Johnson syndrome (DJS) is an autosomal recessive disease characterized by conjugated hyperbilirubinemia. Previous studies of the defects in the human canalicular multispecific organic anion transporter gene (MRP2/cMOAT) in patients with DJS have suggested that the gene defects are responsible for DJS. In this study, we determined the exon/intron structure of the human MRP2/cMOAT gene and further characterized mutations in patients with DJS. The human MRP2/cMOAT gene contains 32 exons, and it has a structure that is highly conserved with that of another ATP- binding-cassette gene, that for a multidrug resistance-associated protein. We then identified three mutations, including two novel ones. All mutations identified to date are in the cytoplasmic domain, which includes the two ATP-binding cassettes and the linker region, or adjacent putative transmembrane domain. Our results confirm that MRP2/cMOAT is the gene responsible for DJS. The finding that mutations are concentrated in the first ATP- binding-cassette domain strongly suggests that a disruption of this region is a critical route to loss of function.
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U2 - 10.1086/302292
DO - 10.1086/302292
M3 - Article
C2 - 10053008
AN - SCOPUS:0033361943
VL - 64
SP - 739
EP - 746
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 3
ER -