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.

Highlights

  • Colony-stimulating factor 1 receptor (CSF1R) regulates the proliferation, differentiation and biological activity of monocyte/macrophage (Mφ) lineages (Stanley et al, 1997)

  • The mRNA harboring this mutation is predicted to escape from non-sensemediated mRNA decay (NMD) by the NMD Esc Predictor (Figure 2A) (Coban-Akdemir et al, 2018)

  • We identified three rare deleterious heterozygous C-terminal CSF1R variants, which were proved to increase the stability of protein in vitro

Read more

Summary

Introduction

Colony-stimulating factor 1 receptor (CSF1R) regulates the proliferation, differentiation and biological activity of monocyte/macrophage (Mφ) lineages (Stanley et al, 1997). CSF1R is expressed in Paneth cells, renal proximal tubule epithelial cells, and placental trophoblasts, indicating a pleiotropic role of CSF1R protein in embryonic development (Arceci et al, 1989, 1992; Pixley and Stanley, 2004; Huynh et al, 2009; Menke et al, 2009). The CSF1R protein includes an extracellular ligand-binding domain and an intracellular tyrosine kinase domain (PTK domain) (Pixley and Stanley, 2004). The extracellular domain of CSF1R binds to ligands such as CSF1 and IL34, which further induces autophosphorylation and protein dimerization (Wang et al, 2012; Stanley and Chitu, 2014). Downstream molecules interact with the intracellular part of CSF1R and are phosphorylated by the PTK domain.

Methods
Results
Conclusion

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call

Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.