A homozygous R148W mutation in Semaphorin 7A causes progressive familial intrahepatic cholestasis
Abstract 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 SEMA...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2021-11-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.202114563 |
| _version_ | 1797285057817214976 |
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| author | Qiong Pan Gang Luo Jiaquan Qu Sheng Chen Xiaoxun Zhang Nan Zhao Jingjing Ding Hong Yang Mingqiao Li Ling Li Ying Cheng Xuan Li Qiaoling Xie Qiao Li Xueqian Zhou Huiling Zou Shijun Fan Lingyun Zou Wei Liu Guohong Deng Shi‐Ying Cai James L Boyer Jin Chai |
| author_facet | Qiong Pan Gang Luo Jiaquan Qu Sheng Chen Xiaoxun Zhang Nan Zhao Jingjing Ding Hong Yang Mingqiao Li Ling Li Ying Cheng Xuan Li Qiaoling Xie Qiao Li Xueqian Zhou Huiling Zou Shijun Fan Lingyun Zou Wei Liu Guohong Deng Shi‐Ying Cai James L Boyer Jin Chai |
| author_sort | Qiong Pan |
| collection | DOAJ |
| description | Abstract 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 SEMA7AR148W 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 SLC10A1S267F allele, but Slc10a1S267F homozygous mice exhibited normal liver function. Similar to the child, Sema7aR145W 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 Sema7aR145W homozygous mice. Further mechanistic studies demonstrated that Sema7aR145W 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, Sema7aR145W homozygous mutation causes intrahepatic cholestasis by reducing hepatic Bsep and Mrp2 expression. |
| first_indexed | 2024-03-07T17:56:44Z |
| format | Article |
| id | doaj.art-566f092f5c7547c2ae4b6f215821f301 |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2024-03-07T17:56:44Z |
| publishDate | 2021-11-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-566f092f5c7547c2ae4b6f215821f3012024-03-02T11:58:34ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842021-11-011311n/an/a10.15252/emmm.202114563A homozygous R148W mutation in Semaphorin 7A causes progressive familial intrahepatic cholestasisQiong Pan0Gang Luo1Jiaquan Qu2Sheng Chen3Xiaoxun Zhang4Nan Zhao5Jingjing Ding6Hong Yang7Mingqiao Li8Ling Li9Ying Cheng10Xuan Li11Qiaoling Xie12Qiao Li13Xueqian Zhou14Huiling Zou15Shijun Fan16Lingyun Zou17Wei Liu18Guohong Deng19Shi‐Ying Cai20James L Boyer21Jin Chai22Cholestatic Liver Diseases Center Department of Gastroenterology Southwest Hospital Third Military Medical University (Army Medical University) Chongqing ChinaCholestatic Liver Diseases Center Department of Gastroenterology Southwest Hospital Third Military Medical University (Army Medical University) Chongqing ChinaCholestatic Liver Diseases Center Department of Gastroenterology Southwest Hospital Third Military Medical University (Army Medical University) Chongqing ChinaDepartment of Pediatrics Southwest Hospital Third Military Medical University (Army Medical University) Chongqing ChinaCholestatic Liver Diseases Center Department of Gastroenterology Southwest Hospital Third Military Medical University (Army Medical University) Chongqing ChinaCholestatic Liver Diseases Center Department of Gastroenterology Southwest Hospital Third Military Medical University (Army Medical University) Chongqing ChinaCholestatic Liver Diseases Center Department of Gastroenterology Southwest Hospital Third Military Medical University (Army Medical University) Chongqing ChinaCholestatic Liver Diseases Center Department of Gastroenterology Southwest Hospital Third Military Medical University (Army Medical University) Chongqing ChinaCholestatic Liver Diseases Center Department of Gastroenterology Southwest Hospital Third Military Medical University (Army Medical University) Chongqing ChinaCholestatic Liver Diseases Center Department of Gastroenterology Southwest Hospital Third Military Medical University (Army Medical University) Chongqing ChinaCholestatic Liver Diseases Center Department of Gastroenterology Southwest Hospital Third Military Medical University (Army Medical University) Chongqing ChinaCholestatic Liver Diseases Center Department of Gastroenterology Southwest Hospital Third Military Medical University (Army Medical University) Chongqing ChinaCholestatic Liver Diseases Center Department of Gastroenterology Southwest Hospital Third Military Medical University (Army Medical University) Chongqing ChinaCholestatic Liver Diseases Center Department of Gastroenterology Southwest Hospital Third Military Medical University (Army Medical University) Chongqing ChinaCholestatic Liver Diseases Center Department of Gastroenterology Southwest Hospital Third Military Medical University (Army Medical University) Chongqing ChinaDepartment of Pediatrics Changsha Hospital for Maternal & Child Health Care Changsha ChinaMedical Research Center Southwest Hospital Third Military Medical University (Army Medical University) Chongqing ChinaBao'an Maternal and Child Health Hospital Jinan University Shenzhen ChinaInstitute of Immunology Third Military Medical University (Army Medical University) Chongqing ChinaDepartment of Infectious Diseases Southwest Hospital Third Military Medical University (Army Medical University) Chongqing ChinaDepartment of Internal Medicine and Liver Center Yale University School of Medicine New Haven CT USADepartment of Internal Medicine and Liver Center Yale University School of Medicine New Haven CT USACholestatic Liver Diseases Center Department of Gastroenterology Southwest Hospital Third Military Medical University (Army Medical University) Chongqing ChinaAbstract 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 SEMA7AR148W 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 SLC10A1S267F allele, but Slc10a1S267F homozygous mice exhibited normal liver function. Similar to the child, Sema7aR145W 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 Sema7aR145W homozygous mice. Further mechanistic studies demonstrated that Sema7aR145W 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, Sema7aR145W homozygous mutation causes intrahepatic cholestasis by reducing hepatic Bsep and Mrp2 expression.https://doi.org/10.15252/emmm.202114563bile acidbile salt export pumpliver injuryprogressive familial intrahepatic cholestasissemaphorin 7A |
| spellingShingle | Qiong Pan Gang Luo Jiaquan Qu Sheng Chen Xiaoxun Zhang Nan Zhao Jingjing Ding Hong Yang Mingqiao Li Ling Li Ying Cheng Xuan Li Qiaoling Xie Qiao Li Xueqian Zhou Huiling Zou Shijun Fan Lingyun Zou Wei Liu Guohong Deng Shi‐Ying Cai James L Boyer Jin Chai A homozygous R148W mutation in Semaphorin 7A causes progressive familial intrahepatic cholestasis EMBO Molecular Medicine bile acid bile salt export pump liver injury progressive familial intrahepatic cholestasis semaphorin 7A |
| title | A homozygous R148W mutation in Semaphorin 7A causes progressive familial intrahepatic cholestasis |
| title_full | A homozygous R148W mutation in Semaphorin 7A causes progressive familial intrahepatic cholestasis |
| title_fullStr | A homozygous R148W mutation in Semaphorin 7A causes progressive familial intrahepatic cholestasis |
| title_full_unstemmed | A homozygous R148W mutation in Semaphorin 7A causes progressive familial intrahepatic cholestasis |
| title_short | A homozygous R148W mutation in Semaphorin 7A causes progressive familial intrahepatic cholestasis |
| title_sort | homozygous r148w mutation in semaphorin 7a causes progressive familial intrahepatic cholestasis |
| topic | bile acid bile salt export pump liver injury progressive familial intrahepatic cholestasis semaphorin 7A |
| url | https://doi.org/10.15252/emmm.202114563 |
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