Heterozygous calcyclin-binding protein/Siah1-interacting protein (CACYBP/SIP) gene pathogenic variant linked to a dominant family with paucity of interlobular bile duct
Heterozygous calcyclin-binding protein/Siah1-interacting protein (CACYBP/SIP) gene pathogenic variant linked to a dominant family with paucity of interlobular bile duct
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杂合钙周期蛋白结合蛋白/Siah1相互作用蛋白（CACYBP/SIP）基因致病性变异与缺乏小叶间胆管的显性家族相关
DOI：
10.1038/s10038-022-01017-0
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发表时间：
2022
影响因子：
3.5
通讯作者：
Hayasaka Kiyoshi
中科院分区：
文献类型：
--
作者：
Kanno Miyako;Suzuki Mitsuyoshi;Tanikawa Ken;Numakura Chikahiko;Matsuzawa Shu-ichi;Niihori Tetsuya;Aoki Yoko;Matsubara Yoichi;Makino Satoshi;Tamiya Gen;Nakano Satoshi;Funayama Ryo;Shirota Matsuyuki;Nakayama Keiko;Mitsui Tetsuo;Hayasaka Kiyoshi
小叶间胆管缺乏(PILBD)是一种异质性疾病，分为综合征性和非综合征性胆管缺乏两类。综合征性PILBD以Alagille综合征的临床表现为特征。非综合征性PILBD是由多种疾病引起的，如代谢和遗传疾病、传染病、炎症和免疫疾病。我们评估了一个以遗传性PILBD为主的家庭，他们在1-2个月大时出现胆汁淤积，但在1岁时自发改善。下一代测序分析显示为CACYBP/SIPp.E177Q杂合致病变异体。钙周期蛋白结合蛋白和Siah1相互作用蛋白形成泛素连接酶复合体，诱导非磷酸化β-连环蛋白的蛋白酶体降解。免疫组织化学分析显示，在婴儿早期，患者肝脏中的钙结合蛋白和β-连环蛋白水平略有下降，到13个月大时几乎恢复正常。CACYBP/SIPp.E177Q致病变异体可能形成更活跃或更稳定的泛素连接酶复合体，促进β-连环蛋白的降解，延缓肝内胆管的成熟。我们的研究结果表明，对β-连环蛋白浓度的准确调节对肝内胆管的发育至关重要，而CACYBP/SIP型致病变异体是PILDB的一个新的病因。
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 heterozygousCACYBP/SIPp.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. TheCACYBP/SIPp.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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影响因子：
7
作者：
Siepel, A;Bejerano, G;Haussler, D
通讯作者：
Haussler, D
影响因子：
5.5
作者：
Sarah B. H. Ng;Emily H. Turner;P. Robertson;Steven Flygare;A. Bigham;Choli Lee;T. Shaffer;Michelle Wong
通讯作者：
Sarah B. H. Ng;Emily H. Turner;P. Robertson;Steven Flygare;A. Bigham;Choli Lee;T. Shaffer;Michelle Wong
影响因子：
2.9
作者：
Lee, Young-Tae;Dimitrova, Yoana N.;Schneider, Gabriela;Ridenour, Whitney B.;Bhattacharya, Shibani;Soss, Sarah E.;Caprioli, Richard M.;Filipek, Anna;Chazin, Walter J.
通讯作者：
Chazin, Walter J.
影响因子：
7
作者：
Cooper, GM;Stone, EA;Sidow, A
通讯作者：
Sidow, A
影响因子：
7
作者：
McKenna, Aaron;Hanna, Matthew;DePristo, Mark A.
通讯作者：
DePristo, Mark A.