Homozygous Mutations in CSF1R Cause a Pediatric-Onset Leukoencephalopathy and Can Result in Congenital Absence of Microglia
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Microglia are CNS-resident macrophages that scavenge debris and regulate immune responses. Proliferation and development of macrophages, including microglia, requires Colony Stimulating Factor 1 Receptor (CSF1R), a gene previously associated with a dominant adult-onset neurological condition (adult-onset leukoencephalopathy with axonal spheroids and pigmented glia). Here, we report two unrelated individuals with homozygous CSF1R mutations whose presentation was distinct from ALSP. Post-mortem examination of an individual with a homozygous splice mutation (c.1754-1G>C) demonstrated several structural brain anomalies, including agenesis of corpus callosum. Immunostaining demonstrated almost complete absence of microglia within this brain, suggesting that it developed in the absence of microglia. The second individual had a homozygous missense mutation (c.1929C>A [p.His643Gln]) and presented with developmental delay and epilepsy in childhood. We analyzed a zebrafish model (csf1r DM) lacking Csf1r function and found that their brains also lacked microglia and had reduced levels of CUX1, a neuronal transcription factor. CUX1+ neurons were also reduced in sections of homozygous CSF1R mutant human brain, identifying an evolutionarily conserved role for CSF1R signaling in production or maintenance of CUX1+ neurons. Since a large fraction of CUX1+ neurons project callosal axons, we speculate that microglia deficiency may contribute to agenesis of the corpus callosum via reduction in CUX1+ neurons. Our results suggest that CSF1R is required for human brain development and establish the csf1r DM fish as a model for microgliopathies. In addition, our results exemplify an under-recognized form of phenotypic expansion, in which genes associated with well-recognized, dominant conditions produce different phenotypes when biallelically mutated.
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Patients with homozygous CSF1R mutations can have a severe leukoencephalopathy with apparent congenital absence of microglia as well as skeletal dysplasia in some patients.
“Recent studies have described patients with homozygous CSF1R mutations causing a severe leukoencephalopathy with apparent congenital absence of microglia as well as skeletal dysplasia in some patients [15, 36].”
From Loss of homeostatic microglial phenotype in CSF1R-related Leukoencephalopathy (2020) · cites this paper as [36]
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- Authors
- Oosterhof, N., Chang, I. J., Karimiani, E. G., Kuil, L. E., Jensen, D. M., Daza, R., Young, E., Astle, L., van der Linde, H. C., Shivaram, G. M., Demmers, J., Latimer, C. S., Keene, C. D., Loter, E., Maroofian, R., van Ham, T. J., Hevner, R. F., & Bennett, J. T.
- Affiliations
- Erasmus MC (NL)
- University of Washington (US)
- St George's, University of London (GB)
- Seattle Children's Research Institute (US)
- Alaska Native Medical Center (US)
- Seattle Children's Hospital (US)
- Corresponding author
- Bennett, James T.
- ORCID
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2019-05
- Volume
- 104
- Issue
- 5
- Pages
- 936-947
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC6506793
- OpenAlex
- W2938531047
- Cited by
- 247
- References
- 16
- Citations by year
- 2026: 20 · 2025: 28 · 2024: 47 · 2023: 27 · 2022: 28 · 2021: 41 · 2020: 34 · 2019: 22
- FWCI
- 13.76
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, other-oa)
- Funders
- Burroughs Wellcome Fund
- National Institutes of Health
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Fetal and Pediatric Neurological Disorders
- Keywords
- CSF1R, agenesis of the corpus callosum, CUX1, phenotypic expansion, biallelic variants, developmental delay, epilepsy, macrophage development, brain development
- MeSH terms
- Congenital Abnormalities, Adult, Animals, Child, Homozygote, Humans, Infant, Infant, Newborn, Mutation, Pedigree, Phenotype, Protein-Tyrosine Kinases, Repressor Proteins, Transcription Factors, Zebrafish, Receptor, Macrophage Colony-Stimulating Factor, Receptors, Granulocyte-Macrophage Colony-Stimulating Factor, Microglia, Homeodomain Proteins, Receptor Protein-Tyrosine Kinases, Zebrafish Proteins, Young Adult, Leukoencephalopathies
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