A kinase-dead Csf1r mutation associated with adult-onset leukoencephalopathy has a dominant inhibitory impact on CSF1R signalling

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dc.contributor.authorStables, J.
dc.contributor.authorGreen, E.K.
dc.contributor.authorSehgal, A.
dc.contributor.authorPatkar, O.L.
dc.contributor.authorKeshvari, S.
dc.contributor.authorTaylor, I.
dc.contributor.authorAshcroft, M.E.
dc.contributor.authorGrabert, K.
dc.contributor.authorWollscheid-Lengeling, E.
dc.contributor.authorSzymkowiak, S.
dc.contributor.authorMcColl, B.W.
dc.contributor.authorAdamson, A.
dc.contributor.authorHumphreys, N.E.
dc.contributor.authorMueller, W.
dc.contributor.authorStarobova, H.
dc.contributor.authorVetter, I.
dc.contributor.authorShabestari, S.K.
dc.contributor.authorBlurton-Jones, M.M.
dc.contributor.authorSummers, K.M.
dc.contributor.authorIrvine, K.M.
dc.contributor.authoret al.
dc.date.issued2022
dc.description.abstractAmino 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.
dc.description.statementofresponsibilityJennifer Stables, Emma K. Green, Anuj Sehgal, Omkar L. Patkar, Sahar Keshvari, Isis Taylor, Maisie E. Ashcroft, Kathleen Grabert, Evi Wollscheid-Lengeling, Stefan Szymkowiak, Barry W. McColl, Antony Adamson, Neil E. Humphreys, Werner Mueller, Hana Starobova, Irina Vetter, Sepideh Kiani Shabestari, Matthew M. Blurton-Jones, Kim M. Summers, Katharine M. Irvine, Clare Pridans and David A. Hume
dc.identifier.citationDevelopment (Cambridge), 2022; 149(8):dev200237-1-dev200237-16
dc.identifier.doi10.1242/dev.200237
dc.identifier.issn0950-1991
dc.identifier.issn1477-9129
dc.identifier.orcidStables, J. [0000-0002-0728-3686]
dc.identifier.urihttps://hdl.handle.net/2440/139948
dc.language.isoen
dc.publisherCompany of Biologists
dc.relation.granthttp://purl.org/au-research/grants/arc/LE100100074
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/GNT1163981
dc.rights© 2022. Published by The Company of Biologists Ltd. T his is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
dc.source.urihttps://doi.org/10.1242/dev.200237
dc.subjectCSF1R; Macrophage; Kinase-dead; Leukoencephalopathy
dc.titleA kinase-dead Csf1r mutation associated with adult-onset leukoencephalopathy has a dominant inhibitory impact on CSF1R signalling
dc.typeJournal article
pubs.publication-statusPublished

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