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Functional inactivation of MDR3 caused by a homozygous ABCB4 missense variant leading to liver failure

Sophia Heinrich1,2, Annika Behrendt3, Malte Sgodda1,4

  • 1Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany.

Frontiers in Genetics
|April 17, 2026
PubMed

Insights

The ABCB4 p.(Arg144Gln) variant causes progressive familial intrahepatic cholestasis (PFIC) by inactivating the MDR3 protein. This study clarifies a variant of uncertain significance, aiding molecular diagnosis of cholestatic liver disease.

Area of Science:

  • Hepatology
  • Genetics
  • Molecular Biology

Background:

  • Progressive familial intrahepatic cholestasis (PFIC) is a rare hereditary liver disorder.
  • Defective hepatobiliary transport, often due to ATP binding cassette 4 (ABCB4) variants, causes PFIC.
  • Many ABCB4 variants are of uncertain significance (VUS), hindering diagnosis.

Purpose of the Study:

  • To functionally characterize the homozygous ABCB4 missense variant c.431G>A (p.(Arg144Gln)).
  • To determine the pathogenicity of the p.(Arg144Gln) variant in ABCB4-associated cholestatic liver disease.

Main Methods:

  • In silico analysis using the Vasor prediction tool.
  • Structural modeling of the MDR3 protein.
  • Immunofluorescence analyses to assess protein localization and function.

Main Results:

  • In silico analysis predicted a high probability of pathogenicity (0.88).
  • Structural modeling indicated disruption of electrostatic interactions essential for MDR3 membrane anchoring.
  • Immunofluorescence showed reduced membrane localization and cytoplasmic retention, indicating loss of function.

Conclusions:

  • The ABCB4 p.(Arg144Gln) variant causes functional inactivation of MDR3, representing a novel pathogenic mutation.
  • Combined genetic, structural, and functional analyses are crucial for characterizing VUS in ABCB4-associated cholestatic liver disease.
Keywords:
ABCB4MDR3 deficiencyfunctional variant reclassificationprogressive familial intrahepatic cholestasisvariant of uncertain significance

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