Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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

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.

This is a preview of subscription content, access via your institution

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

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.

References

  1. Gillen MC, Huppert SS. Liver development. In: Suchy FJ, Sokol RJ, Balistreri WF, editors. Liver disease in children. 5th ed. Cambridge: Cambridge University Press; 2021. p. 1–11.

  2. Strazzabosco M, Fabris L. Development of the bile ducts: essentials for the clinical hepatologist. J Hepatol. 2012;56:1159–70.

    Article  CAS  Google Scholar 

  3. Zong Y, Stanger BZ. Molecular mechanisms of liver and bile duct development. Wiley Interdiscip Rev Dev Biol. 2012;1:643–55.

    Article  CAS  Google Scholar 

  4. Gérard C, Tys J, Lemaigre FP. Gene regulatory networks in differentiation and direct reprogramming of hepatic cells. Semin Cell Dev Biol. 2017;66:43–50.

    Article  Google Scholar 

  5. Meena BL, Khanna R, Bihari C, Rastogi A, Rawat D, Alam S. Bile duct paucity in childhood-spectrum, profile, and outcome. Eur J Pediatr. 2018;177:1261–9.

    Article  CAS  Google Scholar 

  6. Topolska-Woś AM, Chazin WJ, Filipek A. CacyBP/SIP–structure and variety of functions. Biochim Biophys Acta. 2016;1860:79–85.

    Article  Google Scholar 

  7. Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 2009;25:1754–60.

    Article  CAS  Google Scholar 

  8. McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation NDA sequencing date. Genome Res. 2010;20:1297–303.

    Article  CAS  Google Scholar 

  9. DePristo MA, Branks E, Poplin R, Garimella KV, Maguire JR, Hartl C, et al. A framework for variation discovery and genotyping using next-generation DNA sequencing date. Nat Genet. 2011;43:491–8.

    Article  CAS  Google Scholar 

  10. Ng SB, Turner EH, Robertson PD, Flygare SD, Bigham AW, Lee C, et al. Targeted capture and massively parallel sequencing of 12 human exomes. Nature. 2009;461:272–6.

    Article  CAS  Google Scholar 

  11. Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from next-generation sequencing data. Nucleic Acids Res. 2010;38:e164.

    Article  Google Scholar 

  12. Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, et al. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7:248–9.

    Article  CAS  Google Scholar 

  13. Grantham R. Amino acid difference formula to help explain protein evolution. Science. 1974;185:862–4.

    Article  CAS  Google Scholar 

  14. Siepel A, Bejerano G, Pedersen JS, Hinrichs AS, Hou M, Rosenbloom K, et al. Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes. Genome Res. 2005;15:1034–50.

    Article  CAS  Google Scholar 

  15. Cooper GM, Stone EA, Asimenos G, Green ED, Batzoglou S, Sidow A. Distribution and intensity of constraint in mammalian genomic sequence. Genome Res. 2005;15:901–13.

    Article  CAS  Google Scholar 

  16. Cordi S, Godard C, Saandi T, Jacquemin P, Monga SP, Colnot S, et al. Role of β-catenin in development of bile ducts. Differentiation. 2016;91:42–9.

    Article  CAS  Google Scholar 

  17. Tan X, Yuan Y, Zeng G, Apte U, Thompson MD, Cieply B, et al. Beta-catenin deletion in hepatoblasts disrupts hepatic morphogenesis and survival during mouse development. Hepatology. 2008;47:1667–79.

    Article  CAS  Google Scholar 

  18. Yeh TH, Krauland L, Singh V, Zou B, Devaraj P, Stolz DB, et al. Liver-specific beta-catenin knockout mice have bile canalicular abnormalities, bile secretory defect, and intrahepatic cholestasis. Hepatology. 2010;52:1410–9.

    Article  CAS  Google Scholar 

  19. Decaens T, Godard C, de Reyniès A, Rickman DS, Tronche F, Couty JP, et al. Stabilization of beta-catenin affects mouse embryonic liver growth and hepatoblast fate. Hepatology. 2008;47:247–58.

    Article  CAS  Google Scholar 

  20. Matsuzawa SI, Reed JC. Siah-1, SIP, and Ebi collaborate in a novel pathway for beta-catenin degradation linked to p53 responses. Mol Cell. 2001;7:915–26.

    Article  CAS  Google Scholar 

  21. Perugorria MJ, Olaizola P, Labiano I, Esparza-Baquer A, Marzioni M, Marin JJG, et al. Wnt-β-catenin signalling in liver development, health and disease. Nat Rev Gastroenterol Hepatol. 2019;16:121–36.

    Article  CAS  Google Scholar 

  22. Lee YT, Dimitrova YN, Schneider G, Ridenour WB, Bhattacharya S, Soss SE, et al. Structure of the S100A6 complex with a fragment from the C-terminal domain of Siah-1 interacting protein: a novel mode for S100 protein target recognition. Biochemistry. 2008;47:10921–32.

    Article  CAS  Google Scholar 

  23. Fukushima T, Zapata JM, Singha NC, Thomas M, Kress CL, Krajewska M, et al. Critical function for SIP, a ubiquitin E3 ligase component of the beta-catenin degradation pathway, for thymocyte development and G1 checkpoint. Immunity. 2006;24:29–39.

    Article  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Kiyoshi Hayasaka.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

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

Search

Quick links