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[Clinical features and molecular mechanism of infantile cholestasis caused by IFT122 gene variants]

J Q Li1, Y Li2, R D He2

  • 1Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, Shanghai 201102, China.

Zhonghua Er Ke Za Zhi = Chinese Journal of Pediatrics
|December 16, 2025
PubMed

Insights

Genetic variants in the IFT122 gene cause infantile cholestasis by impairing primary cilia formation and function. These IFT122 gene variants disrupt key protein localization, leading to severe liver disease with high gamma-glutamyltransferase (GGT).

Area of Science:

  • Genetics
  • Molecular Biology
  • Pediatric Gastroenterology

Background:

  • Infantile cholestasis is a serious liver condition in infants.
  • Genetic factors play a role in some cholestasis cases.
  • Primary cilia are crucial cellular structures involved in various signaling pathways.

Purpose of the Study:

  • To identify the genetic cause of infantile cholestasis in a specific patient.
  • To investigate how identified gene variants affect primary cilia structure and function.
  • To elucidate the molecular mechanism linking IFT122 gene variants to infantile cholestasis.

Main Methods:

  • Retrospective analysis of clinical data from an infant with cholestasis.
  • Whole-exome sequencing to identify genetic variants in the IFT122 gene.
  • Immunofluorescence staining in cell lines to assess primary cilia defects and protein localization.

Main Results:

  • Identified compound heterozygous variants (c.88G>C and c.240G>C) in the IFT122 gene.
  • These variants significantly reduced cilia formation and altered the localization of ARL13B and INPP5E proteins within cilia.
  • The patient exhibited jaundice, elevated liver enzymes (especially GGT), and characteristic liver pathology.

Conclusions:

  • Compound heterozygous IFT122 gene variants cause infantile cholestasis.
  • These variants impair ciliogenesis and disrupt ARL13B and INPP5E ciliary localization.
  • This molecular dysfunction ultimately leads to high-GGT infantile cholestasis.

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