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Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids 总被引:1,自引:0,他引:1
Rademakers R Baker M Nicholson AM Rutherford NJ Finch N Soto-Ortolaza A Lash J Wider C Wojtas A DeJesus-Hernandez M Adamson J Kouri N Sundal C Shuster EA Aasly J MacKenzie J Roeber S Kretzschmar HA Boeve BF Knopman DS Petersen RC Cairns NJ Ghetti B Spina S Garbern J Tselis AC Uitti R Das P Van Gerpen JA Meschia JF Levy S Broderick DF Graff-Radford N Ross OA Miller BB Swerdlow RH Dickson DW Wszolek ZK 《Nature genetics》2012,44(2):200-205
Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an autosomal-dominant central nervous system white-matter disease with variable clinical presentations, including personality and behavioral changes, dementia, depression, parkinsonism, seizures and other phenotypes. We combined genome-wide linkage analysis with exome sequencing and identified 14 different mutations affecting the tyrosine kinase domain of the colony stimulating factor 1 receptor (encoded by CSF1R) in 14 families with HDLS. In one kindred, we confirmed the de novo occurrence of the mutation. Follow-up sequencing identified an additional CSF1R mutation in an individual diagnosed with corticobasal syndrome. In vitro, CSF-1 stimulation resulted in rapid autophosphorylation of selected tyrosine residues in the kinase domain of wild-type but not mutant CSF1R, suggesting that HDLS may result from partial loss of CSF1R function. As CSF1R is a crucial mediator of microglial proliferation and differentiation in the brain, our findings suggest an important role for microglial dysfunction in HDLS pathogenesis. 相似文献
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