Variants Affecting the C-Terminal of CSF1R Cause Congenital Vertebral Malformation Through a Gain-of-Function Mechanism

Bowen Liu; Sen Zhao; Zihui Yan; Lina Zhao; Jiachen Lin; Shengru Wang; Yuchen Niu; Xiaoxin Li; Guixing Qiu; Deciphering Disorders Involving Scoliosis and COmorbidities (DISCO) study; Terry Jianguo Zhang; Zhihong Wu; Nan Wu

doi:10.3389/fcell.2021.641133

Variants Affecting the C-Terminal of CSF1R Cause Congenital Vertebral Malformation Through a Gain-of-Function Mechanism

Front Cell Dev Biol. 2021 Mar 19:9:641133. doi: 10.3389/fcell.2021.641133. eCollection 2021.

Authors

Bowen Liu^{1

2}, Sen Zhao^{1

2}, Zihui Yan^{1

2

3}, Lina Zhao^{2

4}, Jiachen Lin^{1

2

3}, Shengru Wang^{1

2}, Yuchen Niu^{2

4}, Xiaoxin Li^{2

4}, Guixing Qiu^{1

2}; Deciphering Disorders Involving Scoliosis and COmorbidities (DISCO) study; Terry Jianguo Zhang^{1

2}, Zhihong Wu^{2

4}, Nan Wu^{1

2}

Affiliations

¹ 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.
² Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China.
³ Graduate School of Peking Union Medical College, Beijing, China.
⁴ Medical Research Center, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.

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: C-terminal variant; colony stimulating factor 1 receptor; congenital vertebra malformation; gain-of-function mechanism; zebrafish model.