Clinical phenotype and molecular analysis of a homozygous ABCB11 mutation responsible for progressive infantile cholestasis

J Hum Genet. 2018 May;63(5):569-577. doi: 10.1038/s10038-018-0431-1. Epub 2018 Mar 5.

Abstract

The bile salt export pump (BSEP) plays an important role in biliary secretion. Mutations in ABCB11, the gene encoding BSEP, induce progressive familial intrahepatic cholestasis type 2 (PFIC2), which presents with severe jaundice and liver dysfunction. A less severe phenotype, called benign recurrent intrahepatic cholestasis type 2, is also known. About 200 missense mutations in ABCB11 have been reported. However, the phenotype-genotype correlation has not been clarified. Furthermore, the frequencies of ABCB11 mutations differ between Asian and European populations. We report a patient with PFIC2 carrying a homozygous ABCB11 mutation c.386G>A (p.C129Y) that is most frequently reported in Japan. The pathogenicity of BSEPC129Y has not been investigated. In this study, we performed the molecular analysis of this ABCB11 mutation using cells expressing BSEPC129Y. We found that trafficking of BSEPC129Y to the plasma membrane was impaired and that the expression of BSEPC129Y on the cell surface was significantly lower than that in the control. The amount of bile acids transported via BSEPC129Y was also significantly lower than that via BSEPWT. The transport activity of BSEPC129Y may be conserved because the amount of membrane BSEPC129Y corresponded to the uptake of taurocholate into membrane vesicles. In conclusion, we demonstrated that c.386G>A (p.C129Y) in ABCB11 was a causative mutation correlating with the phenotype of patients with PFIC2, impairment of biliary excretion from hepatocytes, and the absence of canalicular BSEP expression in liver histological assessments. Mutational analysis in ABCB11 could facilitate the elucidation of the molecular mechanisms underlying the development of intrahepatic cholestasis.

Publication types

  • Case Reports
  • Review

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 11 / chemistry
  • ATP Binding Cassette Transporter, Subfamily B, Member 11 / genetics*
  • ATP Binding Cassette Transporter, Subfamily B, Member 11 / metabolism
  • Alleles
  • Cell Line
  • Cholestasis, Intrahepatic / diagnosis*
  • Cholestasis, Intrahepatic / genetics*
  • Disease Progression
  • Female
  • Genetic Association Studies*
  • Hepatocytes / metabolism
  • Homozygote
  • Humans
  • Male
  • Models, Molecular
  • Mutation*
  • Phenotype*
  • Protein Conformation
  • Sequence Analysis, DNA

Substances

  • ABCB11 protein, human
  • ATP Binding Cassette Transporter, Subfamily B, Member 11

Supplementary concepts

  • Cholestasis, progressive familial intrahepatic 2