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Cited by 74Neuroinflammation and Neurodegeneration MechanismsHereditary Neurological DisordersAlzheimer's disease research and treatments

CSF1R mutations in hereditary diffuse leukoencephalopathy with spheroids are loss of function

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Pridans, Clare, Sauter, Kristin A., Baer, Kristin, Kissel, Holger, Hume, David A.·2013·Scientific Reports
DOI 10.1038/srep03013PMC PMC3804858
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Abstract

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) in humans is a rare autosomal dominant disease characterized by giant neuroaxonal swellings (spheroids) within the CNS white matter. Symptoms are variable and can include personality and behavioural changes. Patients with this disease have mutations in the protein kinase domain of the colony-stimulating factor 1 receptor (CSF1R) which is a tyrosine kinase receptor essential for microglia development. We investigated the effects of these mutations on Csf1r signalling using a factor dependent cell line. Corresponding mutant forms of murine Csf1r were expressed on the cell surface at normal levels, and bound CSF1, but were not able to sustain cell proliferation. Since Csf1r signaling requires receptor dimerization initiated by CSF1 binding, the data suggest a mechanism for phenotypic dominance of the mutant allele in HDLS.

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  • Autosomal dominant mutations in CSF1R are the major genetic cause of HDLS.

    “It has been discovered that autosomal dominant mutations in CSF1R, resulting in partial loss of function in CSF-1R signaling, are the major genetic cause of hereditary diffuse leukoencephalopathy with spheroids (HDLS) [22, 40, 44].”

    From Loss of homeostatic microglial phenotype in CSF1R-related Leukoencephalopathy (2020) · cites this paper as [40]

    The Abstract (page not provided) describes HDLS as autosomal dominant, reports CSF1R mutations in multiple affected families, and identifies loss of function in the mutations tested. It does not establish that CSF1R mutations are the major genetic cause of HDLS; no comparison with other genetic causes is reported. (LLM, conf=0.86)

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  • HDLS is related to a loss of function of CSF-1R.

    “Several lines of evidence support our observation that HDLS is related to a loss of function of CSF-1R [40].”

    From Loss of homeostatic microglial phenotype in CSF1R-related Leukoencephalopathy (2020) · cites this paper as [40]

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Research works printed but not linked: 35

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Authors
Pridans, C., Sauter, K. A., Baer, K., Kissel, H., & Hume, D. A.
Affiliations
  • Roslin Institute (GB)
  • Fed­er­al Of­fice of Ad­min­is­tra­tion (DE)
Corresponding author
Hume, David A.
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2013-10-22
Volume
3
Issue
1
Pages
3013-3013
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/srep03013
PMC
PMC3804858
OpenAlex
W2065695164
Cited by
74
References
2
Citations by year
2026: 5 · 2025: 3 · 2024: 12 · 2023: 1 · 2022: 5 · 2021: 12 · 2020: 7 · 2019: 9 · 2018: 4 · 2017: 3 · 2016: 4 · 2015: 6 · 2014: 3
FWCI
2.43
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by-nc-nd)
Funders
Biotechnology and Biological Sciences Research Council (BBS/E/D/20251969)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
hereditary diffuse leukoencephalopathy with spheroids, CSF1R mutation, colony-stimulating factor 1 receptor, loss of function, kinase domain, microglia development, receptor dimerization, phenotypic dominance, autosomal dominant disorder, white matter
MeSH terms
Animals, Cell Line, Cell Survival, Gliosis, Humans, Models, Molecular, Mutation, Protein Binding, Protein Conformation, Signal Transduction, Gene Expression, Receptor, Macrophage Colony-Stimulating Factor, Protein Transport, Mice, Protein Interaction Domains and Motifs, Protein Multimerization, Genetic Association Studies, Leukoencephalopathies

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