期刊
NATURE GENETICS
卷 44, 期 2, 页码 200-205出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.1027
关键词
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资金
- Mayo Benefactor and the Mayo Foundation
- US National Institute of Neurological Disorders and Stroke [P50 NS072187]
- US National Institutes of Health (NIH) [R01 NS057567, IRC2NS070276]
- Mayo Clinic Florida CR [MCF 90052018, MCF 90052030]
- Dystonia Medical Research Foundation
- NIH [R01 NS065782, R01 AG026251, P50 AGO 16574, PHS P30 AG 10133, U24 AG 21886-0151]
- Peebler PSP Research Foundation
- American Heart Association
- James & Esther King Biomedical Research Program
- Florida Department of Health
- Myron and Jane Hanley Award in Stroke research
- Leenaards Foundation
- Swiss Parkinson Foundation
- Mayo Clinic Florida Cerebrovascular Diseases Registry [08-003878]
- Mayo Foundation for Medical Education and Research
- Sven and Dagmar Salens, Stiftelse, Sweden
- Swedish and Gothenburg Societies for the Neurologically Disabled
- Swedish Society of Medicine Gothenburg
- Gothenburg Foundation for Neurological Research
- Bjornsson Foundation, Gothenburg, Sweden
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(1,2). 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. Followup 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.
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