Clinical and genetic characterization of adult‐onset leukoencephalopathy caused by CSF1R mutations

Abstract Objective Mutations in the colony‐stimulating factor 1 receptor gene (CSF1R) were identified as a cause of adult‐onset inherited leukoencephalopathy. The present study aims at investigating the frequency, clinical characteristics, and functional effects of CSF1R mutations in Taiwanese patie...

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Autores principales:	Pei‐Chien Tsai, Jong‐Ling Fuh, Chih‐Chao Yang, Anna Chang, Li‐Ming Lien, Pei‐Ning Wang, Kuan‐Lin Lai, Yu‐Shuen Tsai, Yi‐Chung Lee, Yi‐Chu Liao
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Neurology. Diseases of the nervous system RC346-429
Acceso en línea:	https://doaj.org/article/0b9c32c7d39e4ef39a4af6dac42c3409
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spelling	oai:doaj.org-article:0b9c32c7d39e4ef39a4af6dac42c34092021-11-22T11:11:52ZClinical and genetic characterization of adult‐onset leukoencephalopathy caused by CSF1R mutations2328-950310.1002/acn3.51467https://doaj.org/article/0b9c32c7d39e4ef39a4af6dac42c34092021-11-01T00:00:00Zhttps://doi.org/10.1002/acn3.51467https://doaj.org/toc/2328-9503Abstract Objective Mutations in the colony‐stimulating factor 1 receptor gene (CSF1R) were identified as a cause of adult‐onset inherited leukoencephalopathy. The present study aims at investigating the frequency, clinical characteristics, and functional effects of CSF1R mutations in Taiwanese patients with adult‐onset leukoencephalopathy. Methods Mutational analysis of CSF1R was performed in 149 unrelated individuals with leukoencephalopathy by a targeted resequencing panel covering the entire coding regions of CSF1R. In vitro analysis of the CSF1‐induced autophosphorylation activities of mutant CSF1R proteins was conducted to assess the pathogenicity of the CSF1R mutations. Results Among the eight CSF1R variants identified in this study, five mutations led to a loss of CSF1‐induced autophosphorylation of CSF1R proteins. Four mutations (p.K586*, p.G589R, p.R777Q, and p.R782C) located within the tyrosine kinase domain of CSF1R, whereas the p.T79M mutation resided in the immunoglobulin‐like domain. The five patients carrying the CSF1R mutations developed cognitive decline at age 41, 43, 50, 79, and 86 years, respectively. Psychiatric symptoms and behavior changes were observed in four of the five patients. The executive function and processing speed were severely impaired at an early stage, and their cognitive function deteriorated rapidly within 3–4 years. Diffusion‐restricted lesions at the subcortical regions and bilateral corticospinal tracts were found in three patients. Interpretation CSF1R mutations account for 3.5% (5/149) of the adult‐onset leukoencephalopathy in Taiwan. CSF1R mutations outside the tyrosine kinase domain may also disturb the CSF1R function and lead to the clinical phenotype. Molecular functional validation is important to determine the pathogenicity of novel CSF1R variants.Pei‐Chien TsaiJong‐Ling FuhChih‐Chao YangAnna ChangLi‐Ming LienPei‐Ning WangKuan‐Lin LaiYu‐Shuen TsaiYi‐Chung LeeYi‐Chu LiaoWileyarticleNeurosciences. Biological psychiatry. NeuropsychiatryRC321-571Neurology. Diseases of the nervous systemRC346-429ENAnnals of Clinical and Translational Neurology, Vol 8, Iss 11, Pp 2121-2131 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Neurology. Diseases of the nervous system RC346-429
spellingShingle	Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Neurology. Diseases of the nervous system RC346-429 Pei‐Chien Tsai Jong‐Ling Fuh Chih‐Chao Yang Anna Chang Li‐Ming Lien Pei‐Ning Wang Kuan‐Lin Lai Yu‐Shuen Tsai Yi‐Chung Lee Yi‐Chu Liao Clinical and genetic characterization of adult‐onset leukoencephalopathy caused by CSF1R mutations
description	Abstract Objective Mutations in the colony‐stimulating factor 1 receptor gene (CSF1R) were identified as a cause of adult‐onset inherited leukoencephalopathy. The present study aims at investigating the frequency, clinical characteristics, and functional effects of CSF1R mutations in Taiwanese patients with adult‐onset leukoencephalopathy. Methods Mutational analysis of CSF1R was performed in 149 unrelated individuals with leukoencephalopathy by a targeted resequencing panel covering the entire coding regions of CSF1R. In vitro analysis of the CSF1‐induced autophosphorylation activities of mutant CSF1R proteins was conducted to assess the pathogenicity of the CSF1R mutations. Results Among the eight CSF1R variants identified in this study, five mutations led to a loss of CSF1‐induced autophosphorylation of CSF1R proteins. Four mutations (p.K586*, p.G589R, p.R777Q, and p.R782C) located within the tyrosine kinase domain of CSF1R, whereas the p.T79M mutation resided in the immunoglobulin‐like domain. The five patients carrying the CSF1R mutations developed cognitive decline at age 41, 43, 50, 79, and 86 years, respectively. Psychiatric symptoms and behavior changes were observed in four of the five patients. The executive function and processing speed were severely impaired at an early stage, and their cognitive function deteriorated rapidly within 3–4 years. Diffusion‐restricted lesions at the subcortical regions and bilateral corticospinal tracts were found in three patients. Interpretation CSF1R mutations account for 3.5% (5/149) of the adult‐onset leukoencephalopathy in Taiwan. CSF1R mutations outside the tyrosine kinase domain may also disturb the CSF1R function and lead to the clinical phenotype. Molecular functional validation is important to determine the pathogenicity of novel CSF1R variants.
format	article
author	Pei‐Chien Tsai Jong‐Ling Fuh Chih‐Chao Yang Anna Chang Li‐Ming Lien Pei‐Ning Wang Kuan‐Lin Lai Yu‐Shuen Tsai Yi‐Chung Lee Yi‐Chu Liao
author_facet	Pei‐Chien Tsai Jong‐Ling Fuh Chih‐Chao Yang Anna Chang Li‐Ming Lien Pei‐Ning Wang Kuan‐Lin Lai Yu‐Shuen Tsai Yi‐Chung Lee Yi‐Chu Liao
author_sort	Pei‐Chien Tsai
title	Clinical and genetic characterization of adult‐onset leukoencephalopathy caused by CSF1R mutations
title_short	Clinical and genetic characterization of adult‐onset leukoencephalopathy caused by CSF1R mutations
title_full	Clinical and genetic characterization of adult‐onset leukoencephalopathy caused by CSF1R mutations
title_fullStr	Clinical and genetic characterization of adult‐onset leukoencephalopathy caused by CSF1R mutations
title_full_unstemmed	Clinical and genetic characterization of adult‐onset leukoencephalopathy caused by CSF1R mutations
title_sort	clinical and genetic characterization of adult‐onset leukoencephalopathy caused by csf1r mutations
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/0b9c32c7d39e4ef39a4af6dac42c3409
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Clinical and genetic characterization of adult‐onset leukoencephalopathy caused by CSF1R mutations

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