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- Title
Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids.
- Authors
Rademakers, Rosa; Baker, Matt; Nicholson, Alexandra M; Rutherford, Nicola J; Finch, NiCole; Soto-Ortolaza, Alexandra; Lash, Jennifer; Wider, Christian; Wojtas, Aleksandra; DeJesus-Hernandez, Mariely; Adamson, Jennifer; Kouri, Naomi; Sundal, Christina; Shuster, Elizabeth A; Aasly, Jan; MacKenzie, James; Roeber, Sigrun; Kretzschmar, Hans A; Boeve, Bradley F; Knopman, David S
- Abstract
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.
- Subjects
PERSONALITY change; PROTEIN-tyrosine kinases; AUTOPHOSPHORYLATION; MICROGLIA; MENTAL depression; DEMENTIA
- Publication
Nature Genetics, 2012, Vol 44, Issue 2, p200
- ISSN
1061-4036
- Publication type
Article
- DOI
10.1038/ng.1027