Mutations in the Colony Stimulating Factor 1 Receptor (CSF1R) Gene Cause Hereditary Diffuse Leukoencephalopathy With Spheroids

Nat Genet. 2011 Dec 25;44(2):200-5. doi: 10.1038/ng.1027.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Base Sequence
  • Exome
  • Female
  • Genetic Linkage
  • Humans
  • Leukodystrophy, Globoid Cell / genetics*
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Mutation*
  • Phosphorylation
  • Protein-Tyrosine Kinases / genetics
  • Receptor, Macrophage Colony-Stimulating Factor / genetics*
  • Sequence Analysis, DNA
  • Young Adult

Substances

  • Protein-Tyrosine Kinases
  • Receptor, Macrophage Colony-Stimulating Factor