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  Functional characterization of a novel CSF1R mutation causing hereditary diffuse leukoencephalopathy with spheroids

Kraya, T., Quandt, D., Pfirrmann, T., Kindermann, A., Lampe, L., Schroeter, M. L., et al. (2019). Functional characterization of a novel CSF1R mutation causing hereditary diffuse leukoencephalopathy with spheroids. Molecular Genetics & Genomic Medicine, 7(4): e00595. doi:10.1002/mgg3.595.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0003-8C52-3 Version Permalink: http://hdl.handle.net/21.11116/0000-0003-8CB2-6
Genre: Journal Article

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 Creators:
Kraya, Torsten1, Author
Quandt, Dagmar2, Author
Pfirrmann, Thorsten3, Author
Kindermann, Andrea2, Author
Lampe, Leonie4, 5, Author              
Schroeter, Matthias L.4, 5, Author              
Kohlhase, Jürgen6, Author
Stoevesandt, Dietrich7, Author
Hoffmann, Katrin8, Author
Villavicencio‐Lorini, Pablo8, Author
Affiliations:
1Department of Neurology, Martin Luther University Halle-Wittenberg, Germany, ou_persistent22              
2Institute of Anatomy and Cell Biology, Martin Luther University Halle-Wittenberg, Germany, ou_persistent22              
3Institute of Physiological Chemistry, Martin Luther University Halle-Wittenberg, Germany, ou_persistent22              
4Department Neurology, MPI for Human Cognitive and Brain Sciences, Max Planck Society, ou_634549              
5Clinic for Cognitive Neurology, University of Leipzig, Germany, ou_persistent22              
6SYNLAB Medizinisches Versorgungszentrum Humangenetik Freiburg GmbH, Germany, ou_persistent22              
7Department of Radiology, Martin Luther University Halle-Wittenberg, Germany, ou_persistent22              
8Institute of Human Genetics, Martin Luther University Halle-Wittenberg, Germany, ou_persistent22              

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Free keywords: Clinical diagnostics; Disease; DNA; Gene; Molecular biology; Mutation
 Abstract: Background Colony‐stimulating factor 1 receptor is a tyrosine kinase transmembrane protein that mediates proliferation, differentiation, and survival of monocytes/macrophages and microglia. CSF1R gene mutations cause hereditary diffuse leukoencephalopathy with spheroids (HDLS), an autosomal‐dominantly inherited microgliopathy, leading to early onset dementia with high lethality. Methods By interdisciplinary assessment of a complex neuropsychiatric condition in a 44‐year old female patient, we narrowed down the genetic diagnostic to CSF1R gene sequencing. Flow cytometric analyses of uncultivated peripheral blood monocytes were conducted sequentially to measure the cell surface CSF1 receptor and autophosphorylation levels. Monocyte subpopulations were monitored during disease progression. Results We identified a novel heterozygous deletion–insertion mutation c.2527_2530delinsGGCA, p.(Ile843_Leu844delinsGlyIle) in our patient with initial signs of HDLS. Marginally elevated cell surface CSF1 receptor levels with increased Tyr723 autophosphorylation suggest an enhanced receptor activity. Furthermore, we observed a shift in monocyte subpopulations during disease course. Conclusion Our data indicate a mutation‐related CSF1R gain‐of‐function, accompanied by an altered composition of the peripheral innate immune cells in our patient with HDLS. Since pharmacological targeting of CSF1R with tyrosine kinase inhibitors prevents disease progression in mouse models of neurodegenerative disorders, a potential pharmacological benefit of CSF1R inhibition remains to be elucidated for patients with HDLS.

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Language(s): eng - English
 Dates: 2018-12-302018-08-122019-01-062019-04-15
 Publication Status: Published online
 Pages: -
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 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1002/mgg3.595
PMID: 30729751
PMC: PMC6465730
Other: Epub 2019
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Title: Molecular Genetics & Genomic Medicine
Source Genre: Journal
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Publ. Info: Chichester : Wiley
Pages: - Volume / Issue: 7 (4) Sequence Number: e00595 Start / End Page: - Identifier: ISSN: 2324-9269
CoNE: https://pure.mpg.de/cone/journals/resource/2324-9269