Article (Scientific journals)
A kinase-dead Csf1r mutation associated with adult-onset leukoencephalopathy has a dominant inhibitory impact on CSF1R signalling
Stables, Jennifer; Green, Emma; Sehgal, Anuj et al.
2022In Development, 149 (8)
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Keywords :
CSF1R; Kinase-dead; Leukoencephalopathy; Macrophage
Abstract :
[en] Amino acid substitutions in the kinase domain of the human CSF1R gene are associated with autosomal dominant adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). To model the human disease, we created a disease-associated mutation (pGlu631Lys; E631K) in the mouse Csf1r locus. Homozygous mutation (Csf1rE631K/E631K) phenocopied the Csf1r knockout, with prenatal mortality or severe postnatal growth retardation and hydrocephalus. Heterozygous mutation delayed the postnatal expansion of tissue macrophage populations in most organs. Bone marrow cells from Csf1rE631K/+mice were resistant to CSF1 stimulation in vitro, and Csf1rE631K/+ mice were unresponsive to administration of a CSF1-Fc fusion protein, which expanded tissue macrophage populations in controls. In the brain, microglial cell numbers and dendritic arborisation were reduced in Csf1rE631K/+ mice, as in patients with ALSP. The microglial phenotype is the opposite of microgliosis observed in Csf1r+/- mice. However, we found no evidence of brain pathology or impacts on motor function in aged Csf1rE631K/+ mice. We conclude that heterozygous disease-associated CSF1R mutations compromise CSF1R signalling. We speculate that leukoencephalopathy associated with dominant human CSF1R mutations requires an environmental trigger and/or epistatic interaction with common neurodegenerative disease-associated alleles.
Disciplines :
Genetics & genetic processes
Author, co-author :
Stables, Jennifer;  Mater Research Institute-University of Queensland > Translational Research Institute
Green, Emma;  University of Edinburgh > Centre for Inflammation Research and Simons Initiative for the Developing Brain
Sehgal, Anuj;  Mater Research Institute-University of Queensland > Translational Research Institute
Patkar, Omkar;  Mater Research Institute-University of Queensland > Translational Research Institute
Keshvari, Sahar;  Mater Research Institute-University of Queensland > Translational Research Institute
Taylor, Isis;  Mater Research Institute-University of Queensland > Translational Research Institute
Ashkroft, Maisie;  University of Edinburgh > Centre for Inflammation Research and Simons Initiative for the Developing Brain
Grabert, Kathleen;  Karolinska Institutet > Toxicology Unit, Institute of Environmental Medicine
Wollscheid-Lengeling, Evi ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core
Szymkowiak, Stefan;  University of Edinburgh > UK Dementia Research Institute, Centre for Discovery Brain Sciences
McColl, Barry;  University of Edinburgh > UK Dementia Research Institute, Centre for Discovery Brain Sciences
Adamson, Antony;  University of Manchester > Genome Editing Unit, Faculty of Biology, Medicine and Health
Humphreys, Neil;  University of Manchester > Genome Editing Unit, Faculty of Biology, Medicine and Health
Mueller, Werner;  University of Manchester > Genome Editing Unit, Faculty of Biology, Medicine and Health
Starobova, Hana;  University of Queensland > Institute for Molecular Biosciences & School of Pharmacy
Vetter, Irinia;  University of Queensland > Institute for Molecular Biosciences & School of Pharmacy
Shabestari, Sepideh Kiani;  University of California > Department of Neurobiology & Behavior,
Blurton-Jones, Matthew;  University of California > Department of Neurobiology & Behavior,
Summers, Kim;  Mater Research Institute-University of Queensland > Translational Research Institute
Irvine, Katharine;  Mater Research Institute-University of Queensland > Translational Research Institute
Pridans, Clare;  University of Edinburgh > Centre for Inflammation Research and Simons Initiative for the Developing Brain
Hume, David;  Mater Research Institute-University of Queensland > Translational Research Institute
More authors (12 more) Less
External co-authors :
yes
Language :
English
Title :
A kinase-dead Csf1r mutation associated with adult-onset leukoencephalopathy has a dominant inhibitory impact on CSF1R signalling
Publication date :
15 April 2022
Journal title :
Development
Volume :
149
Issue :
8
Peer reviewed :
Peer reviewed
Available on ORBilu :
since 07 June 2022

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