Exon-intron organization of the human multidrug-resistance protein 2 (MRP2) gene mutated in Dubin-Johnson syndrome

Gastroenterology. 1999 Sep;117(3):653-60. doi: 10.1016/s0016-5085(99)70459-2.

Abstract

Background & aims: The Dubin-Johnson syndrome is characterized by conjugated hyperbilirubinemia and by impaired secretion of anionic conjugates from hepatocytes into bile. Absence of the multidrug-resistance protein 2 (MRP2; symbol ABCC2), an adenosine triphosphate-dependent conjugate export pump, from the hepatocyte canalicular membrane is the molecular basis of this syndrome. The aim of this study was the elucidation of all exon-intron boundaries of the MRP2 gene as a prerequisite for the analysis of mutations in patients with Dubin-Johnson syndrome.

Methods: Exon-intron boundaries of MRP2 were determined, and the amplified exons were screened for mutations. Immunofluorescence microscopy served to localize the MRP2 protein in human liver.

Results: The human MRP2 gene is approximately 45 kilobases long; it contains 32 exons and a high proportion of class 0 introns. In 2 patients with Dubin-Johnson syndrome, we detected a nonsense mutation at codon 1066 and a 6-nucleotide deletion mutation affecting codons 1392-1394. The MRP2 protein was absent from the canalicular membrane of both patients.

Conclusions: The mutations detected so far show that various mutations in the MRP2 gene can lead to the Dubin-Johnson syndrome. The exon-intron boundaries established in this article will facilitate the analysis of additional mutations in the MRP2 gene.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / genetics*
  • ATP Binding Cassette Transporter, Subfamily B / metabolism
  • Adult
  • Amino Acid Sequence
  • DNA Mutational Analysis
  • Exons
  • Female
  • Genes, MDR*
  • Humans
  • Introns
  • Jaundice, Chronic Idiopathic / genetics*
  • Jaundice, Chronic Idiopathic / metabolism
  • Liver / metabolism
  • Membrane Transport Proteins*
  • Microscopy, Fluorescence
  • Molecular Sequence Data
  • Multidrug Resistance-Associated Proteins*
  • Mutation

Substances

  • ATP Binding Cassette Transporter, Subfamily B
  • Membrane Transport Proteins
  • Multidrug Resistance-Associated Proteins
  • multidrug resistance-associated protein 2
  • multidrug resistance-associated protein 1

Associated data

  • GENBANK/AJ132244
  • GENBANK/AJ132287
  • GENBANK/AJ132288
  • GENBANK/AJ132289
  • GENBANK/AJ132290
  • GENBANK/AJ132291
  • GENBANK/AJ132292
  • GENBANK/AJ132293
  • GENBANK/AJ132294
  • GENBANK/AJ132295
  • GENBANK/AJ132296
  • GENBANK/AJ132297
  • GENBANK/AJ132298
  • GENBANK/AJ132299
  • GENBANK/AJ132300
  • GENBANK/AJ132301
  • GENBANK/AJ132302
  • GENBANK/AJ132303
  • GENBANK/AJ132304
  • GENBANK/AJ132305
  • GENBANK/AJ132306
  • GENBANK/AJ132307
  • GENBANK/AJ132308
  • GENBANK/AJ132309
  • GENBANK/AJ132310
  • GENBANK/AJ132311
  • GENBANK/AJ132312
  • GENBANK/AJ132313
  • GENBANK/AJ132314
  • GENBANK/AJ245625