title: Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids.
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.
authors.affiliation: Department of Neuroscience, Mayo Clinic Florida, Jacksonville, Florida, USA. rademakers.rosa@mayo.edu
authors.forename: Rosa
authors.initials: R
authors.lastname: Rademakers
authors.forename: Matt
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authors.lastname: Baker
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Nicholson
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Rutherford
authors.forename: NiCole
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authors.lastname: Finch
authors.forename: Alexandra
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authors.lastname: Soto-Ortolaza
authors.forename: Jennifer
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authors.lastname: Lash
authors.forename: Christian
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authors.lastname: Wider
authors.forename: Aleksandra
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authors.forename: Mariely
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authors.lastname: DeJesus-Hernandez
authors.forename: Jennifer
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authors.lastname: Adamson
authors.forename: Naomi
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authors.lastname: Kouri
authors.forename: Christina
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authors.lastname: Sundal
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Shuster
authors.forename: Jan
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authors.lastname: Aasly
authors.forename: James
authors.initials: J
authors.lastname: MacKenzie
authors.forename: Sigrun
authors.initials: S
authors.lastname: Roeber
authors.forename: Hans A
authors.initials: HA
authors.lastname: Kretzschmar
authors.forename: Bradley F
authors.initials: BF
authors.lastname: Boeve
authors.forename: David S
authors.initials: DS
authors.lastname: Knopman
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Petersen
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Cairns
authors.forename: Bernardino
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authors.lastname: Ghetti
authors.forename: Salvatore
authors.initials: S
authors.lastname: Spina
authors.forename: James
authors.initials: J
authors.lastname: Garbern
authors.forename: Alexandros C
authors.initials: AC
authors.lastname: Tselis
authors.forename: Ryan
authors.initials: R
authors.lastname: Uitti
authors.forename: Pritam
authors.initials: P
authors.lastname: Das
authors.forename: Jay A
authors.initials: JA
authors.lastname: Van Gerpen
authors.forename: James F
authors.initials: JF
authors.lastname: Meschia
authors.forename: Shawn
authors.initials: S
authors.lastname: Levy
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Broderick
authors.forename: Neill
authors.initials: N
authors.lastname: Graff-Radford
authors.forename: Owen A
authors.initials: OA
authors.lastname: Ross
authors.forename: Bradley B
authors.initials: BB
authors.lastname: Miller
authors.forename: Russell H
authors.initials: RH
authors.lastname: Swerdlow
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.forename: Zbigniew K
authors.initials: ZK
authors.lastname: Wszolek
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D059472:Exome; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D007965:Leukodystrophy, Globoid Cell / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000235:genetics*; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: D011505:Protein-Tyrosine Kinases; D016186:Receptor, Macrophage Colony-Stimulating Factor