Variants Affecting the C-Terminal of CSF1R Cause Congenital Vertebral Malformation Through a Gain-of-Function Mechanism
CSF1R encodes the colony-stimulating factor 1 receptor which regulates the proliferation, differentiation, and biological activity of monocyte/macrophage lineages. Pathogenic variants in CSF1R could lead to autosomal dominant adult-onset leukoencephalopathy with axonal spheroids and pigmented glia o...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-03-01
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| Series: | Frontiers in Cell and Developmental Biology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2021.641133/full |
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Article |
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DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Bowen Liu Bowen Liu Sen Zhao Sen Zhao Zihui Yan Zihui Yan Zihui Yan Lina Zhao Lina Zhao Jiachen Lin Jiachen Lin Jiachen Lin Shengru Wang Shengru Wang Yuchen Niu Yuchen Niu Xiaoxin Li Xiaoxin Li Guixing Qiu Guixing Qiu Deciphering Disorders Involving Scoliosis and COmorbidities (DISCO) study Terry Jianguo Zhang Terry Jianguo Zhang Zhihong Wu Zhihong Wu Nan Wu Nan Wu |
| spellingShingle |
Bowen Liu Bowen Liu Sen Zhao Sen Zhao Zihui Yan Zihui Yan Zihui Yan Lina Zhao Lina Zhao Jiachen Lin Jiachen Lin Jiachen Lin Shengru Wang Shengru Wang Yuchen Niu Yuchen Niu Xiaoxin Li Xiaoxin Li Guixing Qiu Guixing Qiu Deciphering Disorders Involving Scoliosis and COmorbidities (DISCO) study Terry Jianguo Zhang Terry Jianguo Zhang Zhihong Wu Zhihong Wu Nan Wu Nan Wu Variants Affecting the C-Terminal of CSF1R Cause Congenital Vertebral Malformation Through a Gain-of-Function Mechanism Frontiers in Cell and Developmental Biology colony stimulating factor 1 receptor congenital vertebra malformation C-terminal variant gain-of-function mechanism zebrafish model |
| author_facet |
Bowen Liu Bowen Liu Sen Zhao Sen Zhao Zihui Yan Zihui Yan Zihui Yan Lina Zhao Lina Zhao Jiachen Lin Jiachen Lin Jiachen Lin Shengru Wang Shengru Wang Yuchen Niu Yuchen Niu Xiaoxin Li Xiaoxin Li Guixing Qiu Guixing Qiu Deciphering Disorders Involving Scoliosis and COmorbidities (DISCO) study Terry Jianguo Zhang Terry Jianguo Zhang Zhihong Wu Zhihong Wu Nan Wu Nan Wu |
| author_sort |
Bowen Liu |
| title |
Variants Affecting the C-Terminal of CSF1R Cause Congenital Vertebral Malformation Through a Gain-of-Function Mechanism |
| title_short |
Variants Affecting the C-Terminal of CSF1R Cause Congenital Vertebral Malformation Through a Gain-of-Function Mechanism |
| title_full |
Variants Affecting the C-Terminal of CSF1R Cause Congenital Vertebral Malformation Through a Gain-of-Function Mechanism |
| title_fullStr |
Variants Affecting the C-Terminal of CSF1R Cause Congenital Vertebral Malformation Through a Gain-of-Function Mechanism |
| title_full_unstemmed |
Variants Affecting the C-Terminal of CSF1R Cause Congenital Vertebral Malformation Through a Gain-of-Function Mechanism |
| title_sort |
variants affecting the c-terminal of csf1r cause congenital vertebral malformation through a gain-of-function mechanism |
| publisher |
Frontiers Media S.A. |
| series |
Frontiers in Cell and Developmental Biology |
| issn |
2296-634X |
| publishDate |
2021-03-01 |
| description |
CSF1R encodes the colony-stimulating factor 1 receptor which regulates the proliferation, differentiation, and biological activity of monocyte/macrophage lineages. Pathogenic variants in CSF1R could lead to autosomal dominant adult-onset leukoencephalopathy with axonal spheroids and pigmented glia or autosomal recessive skeletal dysplasia. In this study, we identified three heterozygous deleterious rare variants in CSF1R from a congenital vertebral malformation (CVM) cohort. All of the three variants are located within the carboxy-terminal region of CSF1R protein and could lead to an increased stability of the protein. Therefore, we established a zebrafish model overexpressing CSF1R. The zebrafish model exhibits CVM phenotypes such as hemivertebral and vertebral fusion. Furthermore, overexpression of the mutated CSF1R mRNA depleted of the carboxy-terminus led to a higher proportion of zebrafish with vertebral malformations than wild-type CSF1R mRNA did (p = 0.03452), implicating a gain-of-function effect of the C-terminal variant. In conclusion, variants affecting the C-terminal of CSF1R could cause CVM though a potential gain-of-function mechanism. |
| topic |
colony stimulating factor 1 receptor congenital vertebra malformation C-terminal variant gain-of-function mechanism zebrafish model |
| url |
https://www.frontiersin.org/articles/10.3389/fcell.2021.641133/full |
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doaj-956b7821da1448dfb0b1f06218b43d482021-03-19T05:21:47ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2021-03-01910.3389/fcell.2021.641133641133Variants Affecting the C-Terminal of CSF1R Cause Congenital Vertebral Malformation Through a Gain-of-Function MechanismBowen Liu0Bowen Liu1Sen Zhao2Sen Zhao3Zihui Yan4Zihui Yan5Zihui Yan6Lina Zhao7Lina Zhao8Jiachen Lin9Jiachen Lin10Jiachen Lin11Shengru Wang12Shengru Wang13Yuchen Niu14Yuchen Niu15Xiaoxin Li16Xiaoxin Li17Guixing Qiu18Guixing Qiu19Deciphering Disorders Involving Scoliosis and COmorbidities (DISCO) studyTerry Jianguo Zhang20Terry Jianguo Zhang21Zhihong Wu22Zhihong Wu23Nan Wu24Nan Wu25Department of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, ChinaBeijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, ChinaDepartment of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, ChinaBeijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, ChinaDepartment of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, ChinaBeijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, ChinaGraduate School of Peking Union Medical College, Beijing, ChinaBeijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, ChinaMedical Research Center, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, ChinaDepartment of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, ChinaBeijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, ChinaGraduate School of Peking Union Medical College, Beijing, ChinaDepartment of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, ChinaBeijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, ChinaBeijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, ChinaMedical Research Center, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, ChinaBeijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, ChinaMedical Research Center, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, ChinaDepartment of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, ChinaBeijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, ChinaDepartment of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, ChinaBeijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, ChinaBeijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, ChinaMedical Research Center, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, ChinaDepartment of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, ChinaBeijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, ChinaCSF1R encodes the colony-stimulating factor 1 receptor which regulates the proliferation, differentiation, and biological activity of monocyte/macrophage lineages. Pathogenic variants in CSF1R could lead to autosomal dominant adult-onset leukoencephalopathy with axonal spheroids and pigmented glia or autosomal recessive skeletal dysplasia. In this study, we identified three heterozygous deleterious rare variants in CSF1R from a congenital vertebral malformation (CVM) cohort. All of the three variants are located within the carboxy-terminal region of CSF1R protein and could lead to an increased stability of the protein. Therefore, we established a zebrafish model overexpressing CSF1R. The zebrafish model exhibits CVM phenotypes such as hemivertebral and vertebral fusion. Furthermore, overexpression of the mutated CSF1R mRNA depleted of the carboxy-terminus led to a higher proportion of zebrafish with vertebral malformations than wild-type CSF1R mRNA did (p = 0.03452), implicating a gain-of-function effect of the C-terminal variant. In conclusion, variants affecting the C-terminal of CSF1R could cause CVM though a potential gain-of-function mechanism.https://www.frontiersin.org/articles/10.3389/fcell.2021.641133/fullcolony stimulating factor 1 receptorcongenital vertebra malformationC-terminal variantgain-of-function mechanismzebrafish model |