Journal
JOURNAL OF HUMAN GENETICS
Volume 66, Issue 12, Pages 1139-1144Publisher
SPRINGERNATURE
DOI: 10.1038/s10038-021-00942-w
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Funding
- Japan Society for the Promotion of Science [18H02932]
- Japan Agency For Medical Research and Development [20bm0804006h0104, 20ek0109486h0001]
- Grants-in-Aid for Scientific Research [18H02932] Funding Source: KAKEN
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Mutations in CSF1R can cause various monogenic disorders, with the new disease BANDDOS showing a more severe and diverse phenotype, including brain abnormalities and skeletal dysplasia. A dose-dependent model is proposed to explain the complex genotype-phenotype association.
Colony-stimulating factor 1 receptor (CSF1R) plays key roles in the development and function of the cells in the monocyte/macrophage lineage, including microglia and osteoclasts. It is well known that mono-allelic mutations of CSF1R cause hereditary diffuse leukoencephalopathy with spheroids (HDLS, OMIM # 221820), an adult-onset progressive neurodegenerative disorder. Recently, a more severe phenotypic spectrum has been identified in individuals with bi-allelic mutations of CSF1R. In addition to leukoencephalopathy of earlier onset than HDLS, the new disease shows brain malformations and skeletal dysplasia compatible with dysosteosclerosis (DOS), thus named brain abnormalities, neurodegeneration, and dysosteosclerosis (BANDDOS, OMIM # 618476). In addition, some individuals with bi-allelic missense mutations of CSF1R have been found to present with incomplete BANDDOS where skeletal dysplasia is absent. In this review, we summarize the monogenic disorders caused by mutations in CSF1R and their mutational spectra, and propose a dose-dependent model to explain the complex genotype-phenotype association.
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