The histidine-loop is essential for transport activity of human MDR3. A novel mutation of MDR3 in a patient with progressive familial intrahepatic cholestasis type 3

Gene. 2012 Sep 10;506(1):141-5. doi: 10.1016/j.gene.2012.06.029. Epub 2012 Jul 3.


Experimental evidence has been provided that a histidine-loop within the nucleotide binding domain of ABC transporter is essential for efficient function of this class of transporter proteins. Here we report the first patient with a mutation of the putative histidine-loop of a human ABC transporter, the multi drug resistance protein 3 (MDR3). The patient presented at the age of 4 years with a history of severe pruritus, elevated serum gamma-glutamyltransferase and bile acid levels since several years suggesting the diagnosis of progressive familial intrahepatic cholestasis type 3 (PFIC-3) due to defects in MDR3. Liver biopsy demonstrated an apparently normal MDR3 expression, however, genetic analysis revealed a novel homozygous mutation in the ABCB4 gene (c.3691C>T) in the patient. This mutation was associated with a change of histidine to tyrosine at amino acid position 1231 of MDR3 (p.H1231Y). As shown by sequence alignment, this amino acid corresponds to the highly conserved histidine of the "H-loop", which is critical for ATP-hydrolysis, suggesting an essential role of histidine 1231 of human MDR3.

Publication types

  • Case Reports

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / chemistry
  • ATP Binding Cassette Transporter, Subfamily B / genetics*
  • ATP Binding Cassette Transporter, Subfamily B / metabolism*
  • Amino Acid Sequence
  • Amino Acid Substitution
  • Base Sequence
  • Bile Ducts, Intrahepatic / metabolism
  • Bile Ducts, Intrahepatic / pathology
  • Binding Sites / genetics
  • Child, Preschool
  • Cholestasis, Intrahepatic / genetics*
  • Cholestasis, Intrahepatic / metabolism*
  • Cholestasis, Intrahepatic / pathology
  • Consanguinity
  • Conserved Sequence
  • DNA Mutational Analysis
  • Histidine / chemistry
  • Homozygote
  • Humans
  • Liver / metabolism
  • Liver / pathology
  • Male
  • Models, Molecular
  • Mutation, Missense*


  • ATP Binding Cassette Transporter, Subfamily B
  • Histidine
  • multidrug resistance protein 3

Supplementary concepts

  • Cholestasis, progressive familial intrahepatic 3