Kraya Torsten, Quandt Dagmar, Pfirrmann Thorsten, Kindermann Andrea, Lampe Leonie, Schroeter Matthias L, Kohlhase Jürgen, Stoevesandt Dietrich, Hoffmann Katrin, Villavicencio-Lorini Pablo
Department of Neurology, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany.
Institute of Anatomy and Cell Biology, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany.
Mol Genet Genomic Med. 2019 Apr;7(4):e00595. doi: 10.1002/mgg3.595. Epub 2019 Feb 6.
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.
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.
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.
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.
集落刺激因子1受体是一种酪氨酸激酶跨膜蛋白，可介导单核细胞/巨噬细胞和小胶质细胞的增殖、分化及存活。CSF1R基因突变会导致伴有球状体的遗传性弥漫性白质脑病（HDLS），这是一种常染色体显性遗传的小胶质细胞病，会导致早发性痴呆且致死率高。
通过对一名44岁女性患者的复杂神经精神状况进行多学科评估，我们将基因诊断范围缩小至CSF1R基因测序。依次对未经培养的外周血单核细胞进行流式细胞术分析，以测量细胞表面CSF1受体及自身磷酸化水平。在疾病进展过程中监测单核细胞亚群。
我们在一名出现HDLS初始症状的患者中鉴定出一种新的杂合缺失插入突变c.2527_2530delinsGGCA，p.(Ile843_Leu844delinsGlyIle)。细胞表面CSF1受体水平略有升高，同时Tyr723自身磷酸化增加，提示受体活性增强。此外，我们在疾病过程中观察到单核细胞亚群发生了变化。
我们的数据表明，在我们的HDLS患者中存在与突变相关的CSF1R功能获得，同时外周固有免疫细胞的组成也发生了改变。由于在神经退行性疾病小鼠模型中，用酪氨酸激酶抑制剂对CSF1R进行药物靶向可阻止疾病进展，因此对于HDLS患者，CSF1R抑制的潜在药理益处仍有待阐明。
