Semaphorin 7A (SEMA7A) is a membrane-bound protein that involves axon growth and other biological processes. SEMA7A mutations are associated with vertebral fracture and Kallmann syndrome. Here, we report a case with a mutation in SEMA7A that displays familial cholestasis. WGS reveals a SEMA7A^R148W homozygous mutation in a female child with elevated levels of serum ALT, AST, and total bile acid (TBA) of unknown etiology. This patient also carried a SLC10A1^S267F allele, but Slc10a1^S267F homozygous mice exhibited normal liver function. Similar to the child, Sema7a^R145W homozygous mice displayed elevated levels of serum ALT, AST, and TBA. Remarkably, liver histology and LC-MS/MS analyses exhibited hepatocyte hydropic degeneration and increased liver bile acid (BA) levels in Sema7a^R145W homozygous mice. Further mechanistic studies demonstrated that Sema7a^R145W mutation reduced the expression of canalicular membrane BA transporters, bile salt export pump (Bsep), and multidrug resistance-associated protein-2 (Mrp2), causing intrahepatic cholestasis in mice. Administration with ursodeoxycholic acid and a dietary supplement glutathione improved liver function in the child. Therefore, Sema7a^R145W homozygous mutation causes intrahepatic cholestasis by reducing hepatic Bsep and Mrp2 expression.

中文翻译：

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Semaphorin 7A 纯合 R148W 突变导致进行性家族性肝内胆汁淤积

Semaphorin 7A (SEMA7A) 是一种膜结合蛋白，涉及轴突生长和其他生物过程。SEMA7A突变与椎骨骨折和卡尔曼综合征相关。在此，我们报告一例SEMA7A突变，表现出家族性胆汁淤积症。WGS 揭示了一名女童存在SEMA7A ^{R148W纯合突变，其血清 ALT、AST 和总胆汁酸 (TBA) 水平升高，但病因不明。}该患者还携带SLC10A1 ^S267F等位基因，但Slc10a1 ^S267F纯合子小鼠表现出正常的肝功能。与儿童相似，Sema7a ^R145W纯合小鼠的血清 ALT、AST 和 TBA 水平升高。值得注意的是，肝脏组织学和 LC-MS/MS 分析显示Sema7a ^R145W纯合小鼠肝细胞水样变性和肝胆汁酸 (BA) 水平升高。进一步的机制研究表明，Sema7a ^R145W突变降低了小管膜 BA 转运蛋白、胆盐输出泵 (Bsep) 和多药耐药相关蛋白 2 (Mrp2) 的表达，导致小鼠肝内胆汁淤积。给予熊去氧胆酸和膳食补充剂谷胱甘肽可改善儿童的肝功能。因此，Sema7a ^R145W纯合突变通过降低肝脏Bsep和Mrp2表达而导致肝内胆汁淤积。