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

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.

MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Neurovetenskaper hsv//swe
MEDICAL AND HEALTH SCIENCES Basic Medicine Neurosciences hsv//eng
Adolescent
Adult
Aged
Aged
80 and over
Base Sequence
Exome
Female
Genetic Linkage
Humans
Leukodystrophy
Globoid Cell
genetics
Male
Middle Aged
Molecular Sequence Data
Mutation
Phosphorylation
Protein-Tyrosine Kinases
genetics
Receptor
Macrophage Colony-Stimulating Factor
genetics
Sequence Analysis
DNA
Young Adult

Baker, Matt (author)
Nicholson, Alexandra M (author)
Rutherford, Nicola J (author)
Finch, NiCole (author)
Soto-Ortolaza, Alexandra (author)
Lash, Jennifer (author)
Wider, Christian (author)
Wojtas, Aleksandra (author)
DeJesus-Hernandez, Mariely (author)
Adamson, Jennifer (author)
Kouri, Naomi (author)
Sundal, ChristinaGothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi,Institute of Neuroscience and Physiology(Swepub:gu)xsuchr (author)
Shuster, Elizabeth A (author)
Aasly, Jan (author)
MacKenzie, James (author)
Roeber, Sigrun (author)
Kretzschmar, Hans A (author)
Boeve, Bradley F (author)
Knopman, David S (author)
Petersen, Ronald C (author)
Cairns, Nigel J (author)
Ghetti, Bernardino (author)
Spina, Salvatore (author)
Garbern, James (author)
Tselis, Alexandros C (author)
Uitti, Ryan (author)
Das, Pritam (author)
Van Gerpen, Jay A (author)
Meschia, James F (author)
Levy, Shawn (author)
Broderick, Daniel F (author)
Graff-Radford, Neill (author)
Ross, Owen A (author)
Miller, Bradley B (author)
Swerdlow, Russell H (author)
Dickson, Dennis W (author)
Wszolek, Zbigniew K (author)
Göteborgs universitetInstitutionen för neurovetenskap och fysiologi (creator_code:org_t)

In:Nature genetics: Springer Science and Business Media LLC44:2, s. 200-51546-17181061-4036

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Neurosciences

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