Open AccessA homozygous R148W mutation in Semaphorin 7A causes progressive familial intrahepatic cholestasis
Author(s) -
Pan Qiong,
Luo Gang,
Qu Jiaquan,
Chen Sheng,
Zhang Xiaoxun,
Zhao Nan,
Ding Jingjing,
Yang Hong,
Li Mingqiao,
Li Ling,
Cheng Ying,
Li Xuan,
Xie Qiaoling,
Li Qiao,
Zhou Xueqian,
Zou Huiling,
Fan Shijun,
Zou Lingyun,
Liu Wei,
Deng Guohong,
Cai ShiYing,
Boyer James L,
Chai Jin
Publication year - 2021
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.202114563
Subject(s) - medicine , china , gastroenterology , family medicine , history , archaeology
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.