title: CSF1R mutations in hereditary diffuse leukoencephalopathy with spheroids are loss of function.
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.
authors.affiliation: 1] The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, Scotland, UK [2].
authors.forename: Clare
authors.initials: C
authors.lastname: Pridans
authors.forename: Kristin A
authors.initials: KA
authors.lastname: Sauter
authors.forename: Kristin
authors.initials: K
authors.lastname: Baer
authors.forename: Holger
authors.initials: H
authors.lastname: Kissel
authors.forename: David A
authors.initials: DA
authors.lastname: Hume
mesh_terms: D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics; D015870:Gene Expression; D056726:Genetic Association Studies; D005911:Gliosis / Q000151:congenital* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D056784:Leukoencephalopathies / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D009154:Mutation; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D021381:Protein Transport; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D016186:Receptor, Macrophage Colony-Stimulating Factor