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Report of a missense TJP2 variant associated to PFIC4 with a pronounced phenotypic variability: Focus on the structural effects on the protein level

Journal of Human Genetics volume 70, pages 331–339 (2025)Cite this article

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Abstract

PFIC4 is a chronic liver disease which cannot be diagnosed based on clinical and biochemical findings with an unpredictable evolution. Here, we reported three consanguineous families with 9 children suffering from intrahepatic cholestasis with low GGT-activity. Three probands were chosen to undergo genetic testing. In silico analyses were conducted to assess the functional impact of the identified variant, along with variants occurring at highly conserved positions within the protein. Additionally, close clinical monitoring was carried. Targeted-NGS sequencing ruled out the diagnosis of PFIC1 and PFIC2. Subsequently, WES allowed the establishment of PFIC4 diagnosis for the three families through the identification of a homozygous TJP2 variant p. Gly532Arg classified as likely pathogenic with a structural damage predicted based on biomolecular modeling and simulation analysis. In-depth in silico analysis of 90 nsSNPs occurring in highly conserved residues in PDZ domains showed 14 ones seems to be relevant in the clinical practice. Clinically, a pronounced phenotypic variability is noted. In conclusion, our study described a homozygous missense PFIC4-related variant with a highlight on the pathogenic power of such types of variants. The clinical evaluation provided information about the importance of close monitoring to prevent liver failure and clarified the unexpected course of PFIC4.

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Acknowledgements

We acknowledge the Center for High Performance Computing (CHPC), South Africa, for providing computational resources to conduct the molecular simulation analysis. And Ribosite Biotechnology company for advanced molecular biology technical support and customized services. This project is carried out under the MOBIDOC scheme, funded by the EU through the SWAFY proJECT and managed by the ANPR.

Author information

Authors and Affiliations

  1. Molecular and Functional Genetics Laboratory, Faculty of Sciences, University of Sfax, Sfax, Tunisia

    Boudour Khabou & Faiza Fakhfakh

  2. Department of Genetics, Farhat Hached University Hospital, Ibn El Jazzar St, Sousse, 4000, Tunisia

    Houcemeddine Othman

  3. Laboratory of cytogenetics, molecular genetics and reproductive biology (LR03SP02), Farhat Hached University Hospital, Ibn El Jazzar St, Sousse, 4000, Tunisia

    Houcemeddine Othman

  4. Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, University of the Witwatersrand, 9 Jubilee Road, Parktown, Johannesburg, 2193, South Africa

    Houcemeddine Othman

  5. Medical Genetic Department, Hédi Chaker University Hospital, Sfax, Tunisia

    Manel Guirat & Hassen Kammoun

  6. Laboratory of Molecular and Cellular Screening Processes (LPCMC), Biotechnology Center of Sfax, Sfax, Tunisia

    Manel Guirat

  7. Faculty of Medicine of Sfax, University of Sfax, Sfax, Tunisia

    Manel Guirat

  8. Pediatric Department, Hedi Chaker University Hospital, Sfax, Tunisia

    Imen Chabchoub, Sana Kmiha & Thouraya Kammoun

  9. Pediatric Department, Tahar Sfar Hospital, Mahdia, Tunisia

    Bahri Mahjoub

  10. Centre of Biotechnology of Sfax (Tunisia), Microorganisms and Biomolecule Laboratory, and Molecular and Cellular Screening Process Laboratory, Sfax, Tunisia

    Rania Abdelhadi

  11. Ksentini Private Laboratory of Cytogenetics of Sfax, Sfax, Tunisia

    Rania Abdelhadi

  12. Ribosite Biotech Company for Research and Development in Biotechnhology, Sfax, Tunisia

    Rania Abdelhadi

  13. Neurological Disorder Research Center, Qatar Biomedical Research Institute (QBRI), Qatar Foundation, Hamad Bin Khalifa University (HBKU), Doha, Qatar

    Afif Ben Mahmoud

  14. Department of Anatomy and Pathological Cytology, Habib Bourguiba Hospital, Sfax, Tunisia

    Rim Kallel & Tahya Sellami Boudawara

  15. Department of Applied Biology, College of sciences, University of Sharjah, Sharjah, United Arab Emirates

    Hassen Hadj Kacem

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  1. Boudour Khabou
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Correspondence to Boudour Khabou.

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Khabou, B., Othman, H., Guirat, M. et al. Report of a missense TJP2 variant associated to PFIC4 with a pronounced phenotypic variability: Focus on the structural effects on the protein level. J Hum Genet 70, 331–339 (2025). https://doi.org/10.1038/s10038-025-01338-w

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