Clinicopathologic characterization and abnormal autophagy of CSF1R-related leukoencephalopathy
Abstract 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 CSF1...
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BMC
2019-12-01
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Series: | Translational Neurodegeneration |
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Online Access: | https://doi.org/10.1186/s40035-019-0171-y |
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Article |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Wo-Tu Tian Fei-Xia Zhan Qing Liu Xing-Hua Luan Chao Zhang Liang Shang Ben-Yan Zhang Si-Jian Pan Fei Miao Jiong Hu Ping Zhong Shi-Hua Liu Ze-Yu Zhu Hai-Yan Zhou Suya Sun Xiao-Li Liu Xiao-Jun Huang Jing-Wen Jiang Jian-Fang Ma Ying Wang Shu-Fen Chen Hui-Dong Tang Sheng-Di Chen Li Cao |
spellingShingle |
Wo-Tu Tian Fei-Xia Zhan Qing Liu Xing-Hua Luan Chao Zhang Liang Shang Ben-Yan Zhang Si-Jian Pan Fei Miao Jiong Hu Ping Zhong Shi-Hua Liu Ze-Yu Zhu Hai-Yan Zhou Suya Sun Xiao-Li Liu Xiao-Jun Huang Jing-Wen Jiang Jian-Fang Ma Ying Wang Shu-Fen Chen Hui-Dong Tang Sheng-Di Chen Li Cao Clinicopathologic characterization and abnormal autophagy of CSF1R-related leukoencephalopathy Translational Neurodegeneration Hereditary diffuse leukoencephalopathy with spheroids CSF1R Autophagy Haploinsufficiency |
author_facet |
Wo-Tu Tian Fei-Xia Zhan Qing Liu Xing-Hua Luan Chao Zhang Liang Shang Ben-Yan Zhang Si-Jian Pan Fei Miao Jiong Hu Ping Zhong Shi-Hua Liu Ze-Yu Zhu Hai-Yan Zhou Suya Sun Xiao-Li Liu Xiao-Jun Huang Jing-Wen Jiang Jian-Fang Ma Ying Wang Shu-Fen Chen Hui-Dong Tang Sheng-Di Chen Li Cao |
author_sort |
Wo-Tu Tian |
title |
Clinicopathologic characterization and abnormal autophagy of CSF1R-related leukoencephalopathy |
title_short |
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_sort |
clinicopathologic characterization and abnormal autophagy of csf1r-related leukoencephalopathy |
publisher |
BMC |
series |
Translational Neurodegeneration |
issn |
2047-9158 |
publishDate |
2019-12-01 |
description |
Abstract 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. |
topic |
Hereditary diffuse leukoencephalopathy with spheroids CSF1R Autophagy Haploinsufficiency |
url |
https://doi.org/10.1186/s40035-019-0171-y |
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doaj-36f4bf5ce79e46218c24661b659049892020-12-06T12:55:18ZengBMCTranslational Neurodegeneration2047-91582019-12-018111310.1186/s40035-019-0171-yClinicopathologic characterization and abnormal autophagy of CSF1R-related leukoencephalopathyWo-Tu Tian0Fei-Xia Zhan1Qing Liu2Xing-Hua Luan3Chao Zhang4Liang Shang5Ben-Yan Zhang6Si-Jian Pan7Fei Miao8Jiong Hu9Ping Zhong10Shi-Hua Liu11Ze-Yu Zhu12Hai-Yan Zhou13Suya Sun14Xiao-Li Liu15Xiao-Jun Huang16Jing-Wen Jiang17Jian-Fang Ma18Ying Wang19Shu-Fen Chen20Hui-Dong Tang21Sheng-Di Chen22Li Cao23Department of Neurology, Rui Jin Hospital & Rui Jin Hospital North, Shanghai Jiao Tong University School of MedicineDepartment of Neurology, Rui Jin Hospital & Rui Jin Hospital North, Shanghai Jiao Tong University School of MedicineDepartment of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC)Department of Neurology, Rui Jin Hospital & Rui Jin Hospital North, Shanghai Jiao Tong University School of MedicineDepartment of Neurology, Rui Jin Hospital & Rui Jin Hospital North, Shanghai Jiao Tong University School of MedicineDepartment of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC)Department of Pathology, Rui Jin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Neurosurgery, Rui Jin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Radiology, Rui Jin Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of MedicineSuzhou Municipal HospitalSuzhou Municipal HospitalDepartment of Neurology, Rui Jin Hospital & Rui Jin Hospital North, Shanghai Jiao Tong University School of MedicineDepartment of Neurology, Rui Jin Hospital & Rui Jin Hospital North, Shanghai Jiao Tong University School of MedicineDepartment of Neurology, Rui Jin Hospital & Rui Jin Hospital North, Shanghai Jiao Tong University School of MedicineDepartment of Neurology, Shanghai Fengxian District Central Hospital, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital South CampusDepartment of Neurology, Rui Jin Hospital & Rui Jin Hospital North, Shanghai Jiao Tong University School of MedicineDepartment of Neurology, Rui Jin Hospital & Rui Jin Hospital North, Shanghai Jiao Tong University School of MedicineDepartment of Neurology, Rui Jin Hospital & Rui Jin Hospital North, Shanghai Jiao Tong University School of MedicineDepartment of Neurology, Rui Jin Hospital & Rui Jin Hospital North, Shanghai Jiao Tong University School of MedicineDepartment of Neurology, Rui Jin Hospital & Rui Jin Hospital North, Shanghai Jiao Tong University School of MedicineDepartment of Neurology, Rui Jin Hospital & Rui Jin Hospital North, Shanghai Jiao Tong University School of MedicineDepartment of Neurology, Rui Jin Hospital & Rui Jin Hospital North, Shanghai Jiao Tong University School of MedicineDepartment of Neurology, Rui Jin Hospital & Rui Jin Hospital North, Shanghai Jiao Tong University School of MedicineAbstract 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.https://doi.org/10.1186/s40035-019-0171-yHereditary diffuse leukoencephalopathy with spheroidsCSF1RAutophagyHaploinsufficiency |