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

Rosa V 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 Carl 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 R Graff Radford, Owen A Ross, Bradley B. Miller, Russell H. Swerdlow, Dennis W Dickson, Zbigniew K Wszolek

Research output: Contribution to journalArticle

258 Citations (Scopus)

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

Fingerprint

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

Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids. / Rademakers, Rosa V; 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 Carl; 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 R; 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, RV, 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, NR, 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 V ; 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 Carl ; 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 R ; 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.
@article{29fcb56c85ac456690cfd18b31505251,
title = "Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids",
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.",
author = "Rademakers, {Rosa V} and Matt Baker and Nicholson, {Alexandra M.} and Rutherford, {Nicola J.} and Nicole Finch and Alexandra Soto-Ortolaza and Jennifer Lash and Christian Wider and Aleksandra Wojtas and Mariely Dejesus-Hernandez and Jennifer Adamson and Naomi Kouri and Christina Sundal and Shuster, {Elizabeth A.} and Jan Aasly and James MacKenzie and Sigrun Roeber and Kretzschmar, {Hans A.} and Boeve, {Bradley F} and Knopman, {David S} and Petersen, {Ronald Carl} and Cairns, {Nigel J.} and Bernardino Ghetti and Salvatore Spina and James Garbern and Tselis, {Alexandros C.} and Ryan Uitti and Pritam Das and {Van Gerpen}, {Jay A} and Meschia, {James F} and Shawn Levy and Broderick, {Daniel F.} and {Graff Radford}, {Neill R} and Ross, {Owen A} and Miller, {Bradley B.} and Swerdlow, {Russell H.} and Dickson, {Dennis W} and Wszolek, {Zbigniew K}",
year = "2012",
month = "2",
doi = "10.1038/ng.1027",
language = "English (US)",
volume = "44",
pages = "200--205",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "2",

}

TY - JOUR

T1 - Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids

AU - Rademakers, Rosa V

AU - Baker, Matt

AU - Nicholson, Alexandra M.

AU - Rutherford, Nicola J.

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 Carl

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 R

AU - Ross, Owen A

AU - Miller, Bradley B.

AU - Swerdlow, Russell H.

AU - Dickson, Dennis W

AU - Wszolek, Zbigniew K

PY - 2012/2

Y1 - 2012/2

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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84856273853&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84856273853&partnerID=8YFLogxK

U2 - 10.1038/ng.1027

DO - 10.1038/ng.1027

M3 - Article

C2 - 22197934

AN - SCOPUS:84856273853

VL - 44

SP - 200

EP - 205

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 2

ER -