Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Nature genetics, 2012-02, Vol.44 (2), p.200-205

Ort / Verlag

New York: Nature Publishing Group US

Erscheinungsjahr

2012

Quelle

MEDLINE

Beschreibungen/Notizen

• Rosa Rademakers and colleagues show that mutations in CSF1R cause hereditary diffuse leukoencephalopathy with spheroids, a central nervous system white-matter disease with variable clinical presentations that include personality and behavioral changes, dementia, depression, parkinsonism and seizures. 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 1 , 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.