title: M-CSF receptor mutations in hereditary diffuse leukoencephalopathy with spheroids impair not only kinase activity but also surface expression.
abstract: The tyrosine kinase Fms, the cell surface receptor for M-CSF and IL-34, is critical for microglial proliferation and differentiation in the brain. Recently, a number of mutations have been identified in Fms as a putative genetic cause of hereditary diffuse leukoencephalopathy with spheroids (HDLS), implying an important role of microglial dysfunction in HDLS pathogenesis. In this study, we initially confirmed that 11 mutations, which reside within the ATP-binding or major tyrosine kinase domain, caused a severe impairment of ligand-induced Fms auto-phosphorylation. Intriguingly, we found that 10 of the 11 mutants also showed a weak cell surface expression, which was associated with a concomitant increase in the low molecular weight hypo-N-glycosylated immature gp130Fms-like species. Indeed, the mutant proteins heavily accumulated to the Golgi-like perinuclear regions. These results indicate that all of the Fms mutations tested severely impair the kinase activity and most of the mutations also impair the trafficking to the cell surface, further suggesting that HDLS is caused by the loss of Fms function.
authors.affiliation: Center for AIDS Research, Kumamoto University, Honjo 2-2-1, Kumamoto-city, Kumamoto 860-0811, Japan.
authors.forename: Masateru
authors.initials: M
authors.lastname: Hiyoshi
authors.forename: Michihiro
authors.initials: M
authors.lastname: Hashimoto
authors.forename: Mamiko
authors.initials: M
authors.lastname: Yukihara
authors.forename: Farzana
authors.initials: F
authors.lastname: Bhuyan
authors.forename: Shinya
authors.initials: S
authors.lastname: Suzu
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D002462:Cell Membrane / Q000201:enzymology; D057809:HEK293 Cells; D006801:Humans; D007378:Interleukins / Q000378:metabolism; D056784:Leukoencephalopathies / Q000235:genetics; D008024:Ligands; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D009154:Mutation; D010766:Phosphorylation; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000235:genetics* / Q000378:metabolism
chemical_list: C529076:IL34 protein, human; D007378:Interleukins; D008024:Ligands; D016173:Macrophage Colony-Stimulating Factor; D000255:Adenosine Triphosphate; D016186:Receptor, Macrophage Colony-Stimulating Factor
keywords: HDLS; IL-34; M-CSF; M-CSF receptor