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. Knopman & 18 others 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

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)200-205
Number of pages6
JournalNature Genetics
Volume44
Issue number2
DOIs
StatePublished - Feb 2012

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Colony-Stimulating Factor Receptors
Macrophage Colony-Stimulating Factor
Mutation
Genes
Exome
Leukoencephalopathies
Parkinsonian Disorders
Hereditary Diffuse Leukoencephalopathy with Spheroids
Protein-Tyrosine Kinases
Tyrosine
Personality
Dementia
Seizures
Phosphotransferases
Central Nervous System
Genome
Depression
Phenotype
Brain

ASJC Scopus subject areas

  • Genetics

Cite this

Rademakers, R., Baker, M., Nicholson, A. M., Rutherford, N. J., Finch, N., Soto-Ortolaza, A., ... Wszolek, Z. K. (2012). Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids. Nature Genetics, 44(2), 200-205. https://doi.org/10.1038/ng.1027

Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids. / Rademakers, Rosa; Baker, Matt; Nicholson, Alexandra M.; Rutherford, Nicola J.; Finch, Nicole; Soto-Ortolaza, Alexandra; Lash, Jennifer; Wider, Christian; Wojtas, Aleksandra; Dejesus-Hernandez, Mariely; Adamson, Jennifer; Kouri, Naomi; Sundal, Christina; Shuster, Elizabeth A.; Aasly, Jan; MacKenzie, James; Roeber, Sigrun; Kretzschmar, Hans A.; Boeve, Bradley F.; Knopman, David S.; Petersen, Ronald C.; Cairns, Nigel J.; Ghetti, Bernardino; Spina, Salvatore; Garbern, James; Tselis, Alexandros C.; Uitti, Ryan; Das, Pritam; Van Gerpen, Jay A.; Meschia, James F.; Levy, Shawn; Broderick, Daniel F.; Graff-Radford, Neill; Ross, Owen A.; Miller, Bradley B.; Swerdlow, Russell H.; Dickson, Dennis W.; Wszolek, Zbigniew K.

In: Nature Genetics, Vol. 44, No. 2, 02.2012, p. 200-205.

Research output: Contribution to journalArticle

Rademakers, R, Baker, M, Nicholson, AM, Rutherford, NJ, Finch, N, Soto-Ortolaza, A, Lash, J, Wider, C, Wojtas, A, Dejesus-Hernandez, M, Adamson, J, Kouri, N, Sundal, C, Shuster, EA, Aasly, J, MacKenzie, J, Roeber, S, Kretzschmar, HA, Boeve, BF, Knopman, DS, Petersen, RC, Cairns, NJ, Ghetti, B, Spina, S, Garbern, J, Tselis, AC, Uitti, R, Das, P, Van Gerpen, JA, Meschia, JF, Levy, S, Broderick, DF, Graff-Radford, N, Ross, OA, Miller, BB, Swerdlow, RH, Dickson, DW & Wszolek, ZK 2012, 'Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids', Nature Genetics, vol. 44, no. 2, pp. 200-205. https://doi.org/10.1038/ng.1027
Rademakers, Rosa ; Baker, Matt ; Nicholson, Alexandra M. ; Rutherford, Nicola J. ; Finch, Nicole ; Soto-Ortolaza, Alexandra ; Lash, Jennifer ; Wider, Christian ; Wojtas, Aleksandra ; Dejesus-Hernandez, Mariely ; Adamson, Jennifer ; Kouri, Naomi ; Sundal, Christina ; Shuster, Elizabeth A. ; Aasly, Jan ; MacKenzie, James ; Roeber, Sigrun ; Kretzschmar, Hans A. ; Boeve, Bradley F. ; Knopman, David S. ; Petersen, Ronald C. ; Cairns, Nigel J. ; Ghetti, Bernardino ; Spina, Salvatore ; Garbern, James ; Tselis, Alexandros C. ; Uitti, Ryan ; Das, Pritam ; Van Gerpen, Jay A. ; Meschia, James F. ; Levy, Shawn ; Broderick, Daniel F. ; Graff-Radford, Neill ; Ross, Owen A. ; Miller, Bradley B. ; Swerdlow, Russell H. ; Dickson, Dennis W. ; Wszolek, Zbigniew K. / Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids. In: Nature Genetics. 2012 ; Vol. 44, No. 2. pp. 200-205.
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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.",
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AU - Rademakers, Rosa

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AU - Nicholson, Alexandra M.

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AU - Finch, Nicole

AU - Soto-Ortolaza, Alexandra

AU - Lash, Jennifer

AU - Wider, Christian

AU - Wojtas, Aleksandra

AU - Dejesus-Hernandez, Mariely

AU - Adamson, Jennifer

AU - Kouri, Naomi

AU - Sundal, Christina

AU - Shuster, Elizabeth A.

AU - Aasly, Jan

AU - MacKenzie, James

AU - Roeber, Sigrun

AU - Kretzschmar, Hans A.

AU - Boeve, Bradley F.

AU - Knopman, David S.

AU - Petersen, Ronald C.

AU - Cairns, Nigel J.

AU - Ghetti, Bernardino

AU - Spina, Salvatore

AU - Garbern, James

AU - Tselis, Alexandros C.

AU - Uitti, Ryan

AU - Das, Pritam

AU - Van Gerpen, Jay A.

AU - Meschia, James F.

AU - Levy, Shawn

AU - Broderick, Daniel F.

AU - Graff-Radford, Neill

AU - Ross, Owen A.

AU - Miller, Bradley B.

AU - Swerdlow, Russell H.

AU - Dickson, Dennis W.

AU - Wszolek, Zbigniew K.

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N2 - 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.

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