Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids

Rosa Rademakers, 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. KnopmanRonald 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

Research output: Contribution to journalArticlepeer-review

321 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)200-205
Number of pages6
JournalNature Genetics
Issue number2
StatePublished - Feb 2012

ASJC Scopus subject areas

  • Genetics


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