Genomic structure of the canalicular multispecific organic anion-transporter gene (MRP2/cMOAT) and mutations in the ATP-binding-cassette region in Dubin-Johnson syndrome.
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.
Toh
S
S
Department of Biochemistry, Kyushu University School of Medicine, Maidashi 3-1-1, Fukuoka 812-8582, Japan.
Wada
M
M
Uchiumi
T
T
Inokuchi
A
A
Makino
Y
Y
Horie
Y
Y
Adachi
Y
Y
Sakisaka
S
S
Kuwano
M
M
D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D027321:Anion Transport Proteins; D001483:Base Sequence; D001663:Bilirubin / Q000097:blood; D002352:Carrier Proteins / Q000235:genetics*; D003306:Coproporphyrins / Q000652:urine; D004252:DNA Mutational Analysis; D017931:DNA Primers; D005091:Exons; D005260:Female; D005838:Genotype; D006801:Humans; D007438:Introns; D007566:Jaundice, Chronic Idiopathic / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D008969:Molecular Sequence Data; D000089762:Multidrug Resistance-Associated Protein 2; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction
C000715087:ABCC2 protein, human; D018528:ATP-Binding Cassette Transporters; D027321:Anion Transport Proteins; D002352:Carrier Proteins; D003306:Coproporphyrins; D017931:DNA Primers; D000089762:Multidrug Resistance-Associated Protein 2; C031467:coproporphyrin I; D001663:Bilirubin