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

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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 phenotypes1,2. 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.

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Figure 1: Neuroimaging and neuropathological findings in HDLS-affected subject FL2-1.
Figure 2: Families with HDLS and CSF1R mutations.
Figure 3: Genomic organization and protein domain structure of CSF1R, with summary of CSF1R mutations.
Figure 4: CSF-1 induces autophosphorylation of wild-type but not mutant CSF1R.


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We thank all family members who participated in this study, D. Gamble for help in coordinating sample and data collection from subjects with ischemic stroke, and R. Ossi for review of brain MRI scans from subjects with ischemic stroke. This work is funded by a Mayo Benefactor and the Mayo Foundation. Mayo Clinic Jacksonville is a Morris K. Udall Parkinson's Disease Research Center of Excellence supported by the US National Institute of Neurological Disorders and Stroke (P50 NS072187). Z.K.W. is partially funded by the US National Institutes of Health (NIH; R01 NS057567 and 1RC2NS070276) and by Mayo Clinic Florida CR programs (MCF 90052018 and MCF 90052030). Z.K.W. is further supported by the family of Carl Edward Bolch Jr. and Susan Bass Bolch, and by Dystonia Medical Research Foundation. R.R. is funded by NIH grants R01 NS065782, R01 AG026251 and P50 AG016574 and by the Peebler PSP Research Foundation. O.A.R. is supported by the American Heart Association, the James & Esther King Biomedical Research Program, the Florida Department of Health and the Myron and Jane Hanley Award in Stroke research. C.W. is supported by the Leenaards Foundation and the Swiss Parkinson Foundation. The Mayo Clinic Florida Cerebrovascular Diseases Registry (IRB no. 08-003878; J.F.M., Principal Investigator) is supported by the Mayo Foundation for Medical Education and Research. C.S. is supported by grants from Sven and Dagmar Saléns, Stiftelse, Sweden; the Swedish and Gothenburg Societies for the Neurologically Disabled; The Swedish Society of Medicine Gothenburg; the Gothenburg Foundation for Neurological Research; and the Björnsson Foundation, Gothenburg, Sweden. This work is further funded by NIH PHS P30 AG 10133 (Indiana Alzheimer Disease Center, to B.G.) and NIH U24 AG 21886-01S1 (National Cell Repository for Alzheimer's disease, to B.G.).

Author information

R.R. and Z.K.W. directed the study. R.R., M.B. and A.M.N. wrote the manuscript. M.B. directed the genetic studies and performed the linkage analysis. A.M.N. directed the functional studies. S.L. performed the exome sequencing and variant calling analysis. M.B., N.J.R., A.S.-O., O.A.R. and A.W. performed the gene sequencing and genotyping studies. A.M.N., N.F., A.W., N.K. and P.D. performed the mutagenesis, cell biology and protein biochemistry studies. Z.K.W. directed the international consortium, assisted by J.L., C.W., C.S., M.D.-H. and J.A. E.A.S., J.A., J.M., S.R., H.A.K., N.J.C., B.G., S.S., A.C.T., J.G., J.A.V.G., B.F.B., D.S.K., R.C.P., D.F.B., J.F.M., R.U., N.G.-R., R.H.S., B.B.M., D.W.D. and Z.K.W. performed clinical evaluations. B.B.M. performed radiological studies. D.W.D. performed neuropathological studies. All authors contributed to manuscript revision.

Correspondence to Rosa Rademakers.

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