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Clinicopathologic characterization and abnormal autophagy of CSF1R-related leukoencephalopathy
BACKGROUND: CSF1R-related leukoencephalopathy, also known as hereditary diffuse leukoencephalopathy with spheroids (HDLS), is a rare white-matter encephalopathy characterized by motor and neuropsychiatric symptoms due to colony-stimulating factor 1 receptor (CSF1R) gene mutation. Few of CSF1R mutati...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6886209/ https://www.ncbi.nlm.nih.gov/pubmed/31827782 http://dx.doi.org/10.1186/s40035-019-0171-y |
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author | Tian, Wo-Tu Zhan, Fei-Xia Liu, Qing Luan, Xing-Hua Zhang, Chao Shang, Liang Zhang, Ben-Yan Pan, Si-Jian Miao, Fei Hu, Jiong Zhong, Ping Liu, Shi-Hua Zhu, Ze-Yu Zhou, Hai-Yan Sun, Suya Liu, Xiao-Li Huang, Xiao-Jun Jiang, Jing-Wen Ma, Jian-Fang Wang, Ying Chen, Shu-Fen Tang, Hui-Dong Chen, Sheng-Di Cao, Li |
author_facet | Tian, Wo-Tu Zhan, Fei-Xia Liu, Qing Luan, Xing-Hua Zhang, Chao Shang, Liang Zhang, Ben-Yan Pan, Si-Jian Miao, Fei Hu, Jiong Zhong, Ping Liu, Shi-Hua Zhu, Ze-Yu Zhou, Hai-Yan Sun, Suya Liu, Xiao-Li Huang, Xiao-Jun Jiang, Jing-Wen Ma, Jian-Fang Wang, Ying Chen, Shu-Fen Tang, Hui-Dong Chen, Sheng-Di Cao, Li |
author_sort | Tian, Wo-Tu |
collection | PubMed |
description | BACKGROUND: CSF1R-related leukoencephalopathy, also known as hereditary diffuse leukoencephalopathy with spheroids (HDLS), is a rare white-matter encephalopathy characterized by motor and neuropsychiatric symptoms due to colony-stimulating factor 1 receptor (CSF1R) gene mutation. Few of CSF1R mutations have been functionally testified and the pathogenesis remains unknown. METHODS: In order to investigate clinical and pathological characteristics of patients with CSF1R-related leukoencephalopathy and explore the potential impact of CSF1R mutations, we analyzed clinical manifestations of 15 patients from 10 unrelated families and performed brain biopsy in 2 cases. Next generation sequencing was conducted for 10 probands to confirm the diagnosis. Sanger sequencing, segregation analysis and phenotypic reevaluation were utilized to substantiate findings. Functional examination of identified mutations was further explored. RESULTS: Clinical and neuroimaging characteristics were summarized. The average age at onset was 35.9 ± 6.4 years (range 24–46 years old). Younger age of onset was observed in female than male (34.2 vs. 39.2 years). The most common initial symptoms were speech dysfunction, cognitive decline and parkinsonian symptoms. One patient also had marked peripheral neuropathy. Brain biopsy of two cases showed typical pathological changes, including myelin loss, axonal spheroids, phosphorylated neurofilament and activated macrophages. Electron microscopy disclosed increased mitochondrial vacuolation and disorganized neurofilaments in ballooned axons. A total of 7 pathogenic variants (4 novel, 3 documented) were identified with autophosphorylation deficiency, among which c.2342C > T remained partial function of autophosphorylation. Western blotting disclosed the significantly lower level of c.2026C > T (p.R676*) than wild type. The level of microtubule associated protein 1 light chain 3-II (LC3-II), a classical marker of autophagy, was significantly lower in mutants expressed cells than wild type group by western blotting and immunofluorescence staining. CONCLUSIONS: Our findings support the loss-of-function and haploinsufficiency hypothesis in pathogenesis. Autophagy abnormality may play a role in the disease. Repairing or promoting the phosphorylation level of mutant CSF1R may shed light on therapeutic targets in the future. However, whether peripheral polyneuropathy potentially belongs to CSF1R-related spectrum deserves further study with longer follow-up and more patients enrolled. TRIAL REGISTRATION: ChiCTR, ChiCTR1800015295. Registered 21 March 2018. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40035-019-0171-y) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-6886209 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-68862092019-12-11 Clinicopathologic characterization and abnormal autophagy of CSF1R-related leukoencephalopathy Tian, Wo-Tu Zhan, Fei-Xia Liu, Qing Luan, Xing-Hua Zhang, Chao Shang, Liang Zhang, Ben-Yan Pan, Si-Jian Miao, Fei Hu, Jiong Zhong, Ping Liu, Shi-Hua Zhu, Ze-Yu Zhou, Hai-Yan Sun, Suya Liu, Xiao-Li Huang, Xiao-Jun Jiang, Jing-Wen Ma, Jian-Fang Wang, Ying Chen, Shu-Fen Tang, Hui-Dong Chen, Sheng-Di Cao, Li Transl Neurodegener Research BACKGROUND: CSF1R-related leukoencephalopathy, also known as hereditary diffuse leukoencephalopathy with spheroids (HDLS), is a rare white-matter encephalopathy characterized by motor and neuropsychiatric symptoms due to colony-stimulating factor 1 receptor (CSF1R) gene mutation. Few of CSF1R mutations have been functionally testified and the pathogenesis remains unknown. METHODS: In order to investigate clinical and pathological characteristics of patients with CSF1R-related leukoencephalopathy and explore the potential impact of CSF1R mutations, we analyzed clinical manifestations of 15 patients from 10 unrelated families and performed brain biopsy in 2 cases. Next generation sequencing was conducted for 10 probands to confirm the diagnosis. Sanger sequencing, segregation analysis and phenotypic reevaluation were utilized to substantiate findings. Functional examination of identified mutations was further explored. RESULTS: Clinical and neuroimaging characteristics were summarized. The average age at onset was 35.9 ± 6.4 years (range 24–46 years old). Younger age of onset was observed in female than male (34.2 vs. 39.2 years). The most common initial symptoms were speech dysfunction, cognitive decline and parkinsonian symptoms. One patient also had marked peripheral neuropathy. Brain biopsy of two cases showed typical pathological changes, including myelin loss, axonal spheroids, phosphorylated neurofilament and activated macrophages. Electron microscopy disclosed increased mitochondrial vacuolation and disorganized neurofilaments in ballooned axons. A total of 7 pathogenic variants (4 novel, 3 documented) were identified with autophosphorylation deficiency, among which c.2342C > T remained partial function of autophosphorylation. Western blotting disclosed the significantly lower level of c.2026C > T (p.R676*) than wild type. The level of microtubule associated protein 1 light chain 3-II (LC3-II), a classical marker of autophagy, was significantly lower in mutants expressed cells than wild type group by western blotting and immunofluorescence staining. CONCLUSIONS: Our findings support the loss-of-function and haploinsufficiency hypothesis in pathogenesis. Autophagy abnormality may play a role in the disease. Repairing or promoting the phosphorylation level of mutant CSF1R may shed light on therapeutic targets in the future. However, whether peripheral polyneuropathy potentially belongs to CSF1R-related spectrum deserves further study with longer follow-up and more patients enrolled. TRIAL REGISTRATION: ChiCTR, ChiCTR1800015295. Registered 21 March 2018. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40035-019-0171-y) contains supplementary material, which is available to authorized users. BioMed Central 2019-12-02 /pmc/articles/PMC6886209/ /pubmed/31827782 http://dx.doi.org/10.1186/s40035-019-0171-y Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Tian, Wo-Tu Zhan, Fei-Xia Liu, Qing Luan, Xing-Hua Zhang, Chao Shang, Liang Zhang, Ben-Yan Pan, Si-Jian Miao, Fei Hu, Jiong Zhong, Ping Liu, Shi-Hua Zhu, Ze-Yu Zhou, Hai-Yan Sun, Suya Liu, Xiao-Li Huang, Xiao-Jun Jiang, Jing-Wen Ma, Jian-Fang Wang, Ying Chen, Shu-Fen Tang, Hui-Dong Chen, Sheng-Di Cao, Li Clinicopathologic characterization and abnormal autophagy of CSF1R-related leukoencephalopathy |
title | Clinicopathologic characterization and abnormal autophagy of CSF1R-related leukoencephalopathy |
title_full | Clinicopathologic characterization and abnormal autophagy of CSF1R-related leukoencephalopathy |
title_fullStr | Clinicopathologic characterization and abnormal autophagy of CSF1R-related leukoencephalopathy |
title_full_unstemmed | Clinicopathologic characterization and abnormal autophagy of CSF1R-related leukoencephalopathy |
title_short | Clinicopathologic characterization and abnormal autophagy of CSF1R-related leukoencephalopathy |
title_sort | clinicopathologic characterization and abnormal autophagy of csf1r-related leukoencephalopathy |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6886209/ https://www.ncbi.nlm.nih.gov/pubmed/31827782 http://dx.doi.org/10.1186/s40035-019-0171-y |
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