Variants Affecting the C-Terminal of CSF1R Cause Congenital Vertebral Malformation Through a Gain-of-Function Mechanism
oleh: 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
| Format: | Article |
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| Diterbitkan: | Frontiers Media S.A. 2021-03-01 |
Deskripsi
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.