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

Miyako Kanno, Mitsuyoshi Suzuki, Ken Tanikawa, Chikahiko Numakura, Shu ichi Matsuzawa, Tetsuya Niihori, Yoko Aoki, Yoichi Matsubara, Satoshi Makino, Gen Tamiya, Satoshi Nakano, Ryo Funayama, Matsuyuki Shirota, Keiko Nakayama, Tetsuo Mitsui, Kiyoshi Hayasaka

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)393-397
Number of pages5
JournalJournal of Human Genetics
Volume67
Issue number7
DOIs
Publication statusPublished - 2022 Jul

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