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Heterozygous calcyclin-binding protein/Siah1-interacting protein (CACYBP/SIP) gene pathogenic variant linked to a dominant family with paucity of interlobular bile duct

Journal of Human Genetics volume 67, pages 393–397 (2022)Cite this article

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Abstract

Paucity of interlobular bile ducts (PILBD) is a heterogeneous disorder classified into two categories, syndromic and non-syndromic bile duct paucity. Syndromic PILBD is characterized by the presence of clinical manifestations of Alagille syndrome. Non-syndromic PILBD is caused by multiple diseases, such as metabolic and genetic disorders, infectious diseases, and inflammatory and immune disorders. We evaluated a family with a dominantly inherited PILBD, who presented with cholestasis at 1–2 months of age but spontaneously improved by 1 year of age. Next-generation sequencing analysis revealed a heterozygous CACYBP/SIP p.E177Q pathogenic variant. Calcyclin-binding protein and Siah1 interacting protein (CACYBP/SIP) form a ubiquitin ligase complex and induce proteasomal degradation of non-phosphorylated β-catenin. Immunohistochemical analysis revealed a slight decrease in CACYBP and β-catenin levels in the liver of patients in early infancy, which almost normalized by 13 months of age. The CACYBP/SIP p.E177Q pathogenic variant may form a more active or stable ubiquitin ligase complex that enhances the degradation of β-catenin and delays the maturation of intrahepatic bile ducts. Our findings indicate that accurate regulation of the β-catenin concentration is essential for the development of intrahepatic bile ducts and CACYBP/SIP pathogenic variant is a novel cause of PILDB.

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Fig. 1: Network driving cholangiocyte differentiation from hepatoblasts.
Fig. 2: Family pedigree.
Fig. 3: Immunohistochemical analysis of the liver specimens.
Fig. 4: Ubiquitination of non-phosphorylated β-catenin and CACYBP/SIP regulation with S100A6.

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Acknowledgements

The authors would like to thank Seiichi Kagimoto (Residential Facility for Handicapped Children, Cayolin’s Residence) and Tatsuki Mizuochi (Department of Pediatrics and Child Health, Kurume University School of Medicine) for their useful information and helpful advice, and Hiroshi Nittono and Hajime Takei (Junshin Clinic, Bile Acid Institute) for analyzing the bile acid levels.

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  1. These authors contributed equally: Miyako Kanno, Mitsuyoshi Suzuki.

Authors and Affiliations

  1. Department of Pediatrics, Yamagata University School of Medicine, Yamagata, Japan

    Miyako Kanno, Chikahiko Numakura, Tetsuo Mitsui & Kiyoshi Hayasaka

  2. Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan

    Mitsuyoshi Suzuki & Satoshi Nakano

  3. Departments of Pathology, Kurume University School of Medicine, Kurume, Fukuoka, Japan

    Ken Tanikawa

  4. Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Shu-ichi Matsuzawa

  5. Department of Medical Genetics, Tohoku University Graduate School of Medicine, Sendai, Japan

    Tetsuya Niihori & Yoko Aoki

  6. National Center for Child Health and Development, Setagaya, Tokyo, Japan

    Yoichi Matsubara

  7. Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan

    Satoshi Makino & Gen Tamiya

  8. Statistical Genetics Team, RIKEN Center for Advanced Intelligence Project, Tokyo, Japan

    Gen Tamiya

  9. Division of Cell Proliferation, ART, Tohoku University Graduate School of Medicine, Sendai, Japan

    Ryo Funayama & Keiko Nakayama

  10. Division of Interdisciplinary Medical Sciences, ART, Tohoku University Graduate School of Medicine, Sendai, Japan

    Matsuyuki Shirota

  11. Department of Pediatrics, Miyukikai Hospital, Social Medical Corporation Miyuki, Kaminoyama, Japan

    Kiyoshi Hayasaka

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  1. Miyako Kanno
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Correspondence to Kiyoshi Hayasaka.

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Kanno, M., Suzuki, M., Tanikawa, K. et al. Heterozygous calcyclin-binding protein/Siah1-interacting protein (CACYBP/SIP) gene pathogenic variant linked to a dominant family with paucity of interlobular bile duct. J Hum Genet 67, 393–397 (2022). https://doi.org/10.1038/s10038-022-01017-0

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  • DOI: https://doi.org/10.1038/s10038-022-01017-0

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