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Using Multi-fluorinated Bile Acids and In Vivo Magnetic Resonance Imaging to Measure Bile Acid Transport
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Published on: November 27, 2016

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Exon-skipping and mRNA decay in human liver tissue: molecular consequences of pathogenic bile salt export pump

Carola Dröge1, Heiner Schaal2, Guido Engelmann3

  • 1Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital, Heinrich Heine University, Düsseldorf, Germany.

Scientific Reports
|April 27, 2016
PubMed

Insights

This study investigates bile salt export pump (BSEP) mutations in progressive familial intrahepatic cholestasis type 2 (PFIC-2). We found nonsense-mediated mRNA decay for frameshift mutations and partial exon skipping for a splice-site mutation, impacting BSEP function.

Area of Science:

  • Hepatology
  • Genetics
  • Molecular Biology

Background:

  • Bile salt export pump (BSEP) is crucial for bile formation.
  • Over 150 mutations in the BSEP gene cause progressive familial intrahepatic cholestasis type 2 (PFIC-2).
  • Specific characterization of BSEP mutations and their molecular consequences is limited.

Purpose of the Study:

  • To investigate the molecular mechanisms of two distinct BSEP mutations in PFIC-2 patients.
  • To analyze the impact of a splice-site mutation (c.150+3A>C) and a frameshift mutation (c.2783_2787dup5) on BSEP mRNA and protein.
  • To understand how these mutations affect BSEP function and contribute to cholestasis.

Main Methods:

  • Analysis of liver tissues from two PFIC-2 patients with compound heterozygous BSEP mutations.
  • Minigene system and mRNA sequencing to study splicing alterations.
  • Immunofluorescence to assess BSEP protein expression.

Main Results:

  • The splice-site mutation c.150+3A>C led to complete skipping of exon 3 in a minigene system.
  • In one patient, the frameshift mutation c.2783_2787dup5 triggered nonsense-mediated mRNA decay (NMD).
  • Despite mutations, detectable BSEP mRNA and protein were observed, with splicing outcomes varying based on genomic and cellular context.

Conclusions:

  • Evidence for effective NMD caused by a BSEP frameshift mutation.
  • Evidence for partial exon skipping induced by the BSEP splice-site mutation c.150+3A>C.
  • Splicing regulation presents a potential therapeutic avenue for BSEP-related liver diseases.

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