Genomic structure of the canalicular multispecific organic anion-transporter gene (MRP2/cMOAT) and mutations in the ATP-binding-cassette region in Dubin-Johnson syndrome

Am J Hum Genet. 1999 Mar;64(3):739-46. doi: 10.1086/302292.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / genetics*
  • Adult
  • Aged
  • Aged, 80 and over
  • Amino Acid Sequence
  • Anion Transport Proteins
  • Base Sequence
  • Bilirubin / blood
  • Carrier Proteins / genetics*
  • Coproporphyrins / urine
  • DNA Mutational Analysis
  • DNA Primers
  • Exons
  • Female
  • Genotype
  • Humans
  • Introns
  • Jaundice, Chronic Idiopathic / genetics*
  • Male
  • Middle Aged
  • Models, Genetic
  • Molecular Sequence Data
  • Phenotype
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • ATP-Binding Cassette Transporters
  • Anion Transport Proteins
  • Carrier Proteins
  • Coproporphyrins
  • DNA Primers
  • coproporphyrin I
  • Bilirubin

Associated data

  • GENBANK/U63970