A homozygous R148W mutation in Semaphorin 7A causes progressive familial intrahepatic cholestasis.
A homozygous R148W mutation in Semaphorin 7A causes progressive familial intrahepatic cholestasis.
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Semaphorin 7A 中的纯合 R148W 突变导致进行性家族性肝内胆汁淤积
DOI：
10.15252/emmm.202114563
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发表时间：
2021-11-08
影响因子：
11.1
通讯作者：
Chai J
中科院分区：
文献类型：
--
作者：
Pan Q;Luo G;Qu J;Chen S;Zhang X;Zhao N;Ding J;Yang H;Li M;Li L;Cheng Y;Li X;Xie Q;Li Q;Zhou X;Zou H;Fan S;Zou L;Liu W;Deng G;Cai SY;Boyer JL;Chai J
信号素7A(Semaphorin 7A，SEMA7A)是一种膜结合蛋白，参与轴突生长等生物学过程。SEMA7A突变与脊椎骨折和卡尔曼综合征有关。在这里，我们报告了一例SEMA7A突变，表现为家族性胆汁淤积症。WGS发现一名女性儿童存在SEMA7A R148W纯合子突变，其血清ALT、AST和总胆汁酸(TBA)水平升高，病因不明。该患者也携带SLC10A1 S267F等位基因，但SLC10a1 S267F纯合子小鼠肝功能正常。与孩子类似，Sema7a R145W纯合子小鼠显示出血清ALT、AST和TBA水平升高。值得注意的是，肝组织学和LC-MS/MS分析显示，在Sema7a R145W纯合子小鼠中，肝细胞水变性和肝脏胆汁酸(BA)水平升高。进一步的机制研究表明，Sema7a R145W突变降低了小鼠肝内胆汁淤积的小管膜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。给予熊去氧胆酸和膳食补充剂谷胱甘肽改善了儿童的肝功能。因此，Sema7a R145W纯合子突变通过降低肝脏BSEP和MRP2的表达而导致肝内胆汁淤积。一种新的进行性家族性肝内胆汁淤积症(PFIC)是由SEMA7A纯合子R148W突变引起的。初步的机制研究表明，该突变降低了肝小管膜胆汁酸(BA)外流转运蛋白BSEP和MRP2的表达，导致肝内胆汁淤积。
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. A new type of progressive familial intrahepatic cholestasis (PFIC) was caused by the homozygous R148W mutation in SEMA7A. Preliminary mechanistic studies revealed that the mutation reduced hepatic expression of canalicular membrane bile acid (BA) efflux transporters Bsep and Mrp2, resulting in intrahepatic cholestasis.