Type of mutations
Table 1. The CSF1Rmutations reported in BANDDOS. [1]
[1] Dulski J, Souza J, Santos ML, Wszolek ZK. Brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS): new cases, systematic literature review, and associations with CSF1R-ALSP. Orphanet J Rare Dis. 2023;18(1):160.
Suspected pathophysiologic mechanism
CSF1R is a receptor tyrosine kinase and has six tyrosine residues. Ligand engagement of CSF1R induces dimerization and auto-phosphorylation of the tyrosine residues, which further activates the downstream kinase signaling pathways involved in the survival, proliferation, differentiation, adhesion, and motility of the monocyte/macrophage lineages including microglia and osteoclasts(as detailed in Figure 1). If the CSF1Rgene becomes mutated, it will directly impair the function of microglia and osteoclasts.
Figure 1. Structure and function of CSF1R protein. [2]
[2] Guo L, Ikegawa S. From HDLS to BANDDOS: fast-expanding phenotypic spectrum of disorders caused by mutations in CSF1R. J Hum Genet. 2021;66(12):1139-1144.
Genetic testing
(a) Whole-exome sequencing was performed on patients to identify potential pathogenic variants in the CSF1Rgene
(b) Sanger sequencing was used to validate the identified CSF1Rvariants and their segregation within the pedigrees.
(c) Pathogenicity assessment of the CSF1Rvariants was conducted by querying four databases: clinvar, 1000 Genomes, gnomAD, and HGMD.
(d) RT-PCR analysis confirmed aberrant splicing of the CSF1Rgene in affected patients.
