Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids.
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2012
- doi: 10.1038/ng.1027
- issn: 1061-4036
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Phenotypes Tyrosine protein kinase Tyrosine kinase Hydroxyaryl-protein kinase Tyrosine-specific protein kinase Tyrosylprotein kinase Searches and seizures--Law and legislation Seizures Personality traits Personal identity Personology Personality theory Traits, Personality Paralysis agitans Shaking palsy Palsy, Shaking Parkinson disease Parkinsonism Family Family structure Families--Social aspects Families--Social conditions Family life Structure, Family Family relationships Relationships, Family Aphrenia Dementias Athymia Aphronesia Nervous system, Central Cerebrum Mind Biography--Psychology Personality Biography--Character Methods of analysis Analysis and chemistry Analytical methods Chemical analysis Analysis methods Analysis and examination illnessCiter ce document
R. Rademakers et al., « Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids. », Serveur académique Lausannois, ID : 10.1038/ng.1027
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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.