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.
Rosa Rademakers  1 ,  Matt Baker ,  Alexandra M Nicholson ,  Nicola J Rutherford ,  NiCole Finch ,  Alexandra Soto-Ortolaza ,  Jennifer Lash ,  Christian Wider ,  Aleksandra Wojtas ,  Mariely DeJesus-Hernandez ,  Jennifer Adamson ,  Naomi Kouri ,  Christina Sundal ,  Elizabeth A Shuster ,  Jan Aasly ,  James MacKenzie ,  Sigrun Roeber ,  Hans A Kretzschmar ,  Bradley F Boeve ,  David S Knopman ,  Ronald C Petersen ,  Nigel J Cairns ,  Bernardino Ghetti ,  Salvatore Spina ,  James Garbern ,  Alexandros C Tselis ,  Ryan Uitti ,  Pritam Das ,  Jay A Van Gerpen ,  James F Meschia ,  Shawn Levy ,  Daniel F Broderick ,  Neill Graff-Radford ,  Owen A Ross ,  Bradley B Miller ,  Russell H Swerdlow ,  Dennis W Dickson ,  Zbigniew K Wszolek
Affiliations
  • 1. Department of Neuroscience, Mayo Clinic Florida, Jacksonville, Florida, USA. [email protected]
PMID: 22197934 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.