Frontiers in Cell and Developmental Biology (Mar 2021)
Variants Affecting the C-Terminal of CSF1R Cause Congenital Vertebral Malformation Through a Gain-of-Function Mechanism
- 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
Affiliations
- Bowen Liu
- Department 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, China
- Bowen Liu
- Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China
- Sen Zhao
- Department 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, China
- Sen Zhao
- Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China
- Zihui Yan
- Department 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, China
- Zihui Yan
- Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China
- Zihui Yan
- Graduate School of Peking Union Medical College, Beijing, China
- Lina Zhao
- Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China
- Lina Zhao
- Medical Research Center, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Jiachen Lin
- Department 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, China
- Jiachen Lin
- Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China
- Jiachen Lin
- Graduate School of Peking Union Medical College, Beijing, China
- Shengru Wang
- Department 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, China
- Shengru Wang
- Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China
- Yuchen Niu
- Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China
- Yuchen Niu
- Medical Research Center, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Xiaoxin Li
- Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China
- Xiaoxin Li
- Medical Research Center, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Guixing Qiu
- Department 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, China
- Guixing Qiu
- Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China
- Deciphering Disorders Involving Scoliosis and COmorbidities (DISCO) study
- Terry Jianguo Zhang
- Department 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, China
- Terry Jianguo Zhang
- Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China
- Zhihong Wu
- Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China
- Zhihong Wu
- Medical Research Center, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Nan Wu
- Department 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, China
- Nan Wu
- Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China
- DOI
- https://doi.org/10.3389/fcell.2021.641133
- Journal volume & issue
-
Vol. 9
Abstract
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.
Keywords
- colony stimulating factor 1 receptor
- congenital vertebra malformation
- C-terminal variant
- gain-of-function mechanism
- zebrafish model
