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Clinical spectrum and genetic landscape for hereditary spastic paraplegias in China
BACKGROUND: Hereditary spastic paraplegias (HSP) is a heterogeneous group of rare neurodegenerative disorders affecting the corticospinal tracts. To date, more than 78 HSP loci have been mapped to cause HSP. However, both the clinical and mutational spectrum of Chinese patients with HSP remained unc...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6035405/ https://www.ncbi.nlm.nih.gov/pubmed/29980238 http://dx.doi.org/10.1186/s13024-018-0269-1 |
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author | Dong, En-Lin Wang, Chong Wu, Shuang Lu, Ying-Qian Lin, Xiao-Hong Su, Hui-Zhen Zhao, Miao He, Jin Ma, Li-Xiang Wang, Ning Chen, Wan-Jin Lin, Xiang |
author_facet | Dong, En-Lin Wang, Chong Wu, Shuang Lu, Ying-Qian Lin, Xiao-Hong Su, Hui-Zhen Zhao, Miao He, Jin Ma, Li-Xiang Wang, Ning Chen, Wan-Jin Lin, Xiang |
author_sort | Dong, En-Lin |
collection | PubMed |
description | BACKGROUND: Hereditary spastic paraplegias (HSP) is a heterogeneous group of rare neurodegenerative disorders affecting the corticospinal tracts. To date, more than 78 HSP loci have been mapped to cause HSP. However, both the clinical and mutational spectrum of Chinese patients with HSP remained unclear. In this study, we aim to perform a comprehensive analysis of clinical phenotypes and genetic distributions in a large cohort of Chinese HSP patients, and to elucidate the primary pathogenesis in this population. METHODS: We firstly performed next-generation sequencing targeting 149 genes correlated with HSP in 99 index cases of our cohort. Multiplex ligation-dependent probe amplification testing was further carried out among those patients without known disease-causing gene mutations. We simultaneously performed a retrospective study on the reported patients exhibiting HSP in other Chinese cohorts. All clinical and molecular characterization from above two groups of Chinese HSP patients were analyzed and summarized. Eventually, we further validated the cellular changes in fibroblasts of two major spastic paraplegia (SPG) patients (SPG4 and SPG11) in vitro. RESULTS: Most patients of ADHSP (94%) are pure forms, whereas most patients of ARHSP (78%) tend to be complicated forms. In ADHSP, we found that SPG4 (79%) was the most prevalent, followed by SPG3A (11%), SPG6 (4%) and SPG33 (2%). Subtle mutations were the common genetic cause for SPG4 patients and most of them located in AAA cassette domain of spastin protein. In ARHSP, the most common subtype was SPG11 (53%), followed by SPG5 (32%), SPG35 (6%) and SPG46 (3%). Moreover, haplotype analysis showed a unique haplotype was shared in 14 families carrying c.334C > T (p.R112(*)) mutation in CYP7B1 gene, suggesting the founder effect. Functionally, we observed significantly different patterns of mitochondrial dynamics and network, decreased mitochondrial membrane potential (Δψm), increased reactive oxygen species and reduced ATP content in SPG4 fibroblasts. Moreover, we also found the enlargement of LAMP1-positive organelles and abnormal accumulation of autolysosomes in SPG11 fibroblasts. CONCLUSIONS: Our study present a comprehensive clinical spectrum and genetic landscape for HSP in China. We have also provided additional evidences for mitochondrial and autolysosomal-mediated pathways in the pathogenesis of HSP. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13024-018-0269-1) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-6035405 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-60354052018-07-09 Clinical spectrum and genetic landscape for hereditary spastic paraplegias in China Dong, En-Lin Wang, Chong Wu, Shuang Lu, Ying-Qian Lin, Xiao-Hong Su, Hui-Zhen Zhao, Miao He, Jin Ma, Li-Xiang Wang, Ning Chen, Wan-Jin Lin, Xiang Mol Neurodegener Research Article BACKGROUND: Hereditary spastic paraplegias (HSP) is a heterogeneous group of rare neurodegenerative disorders affecting the corticospinal tracts. To date, more than 78 HSP loci have been mapped to cause HSP. However, both the clinical and mutational spectrum of Chinese patients with HSP remained unclear. In this study, we aim to perform a comprehensive analysis of clinical phenotypes and genetic distributions in a large cohort of Chinese HSP patients, and to elucidate the primary pathogenesis in this population. METHODS: We firstly performed next-generation sequencing targeting 149 genes correlated with HSP in 99 index cases of our cohort. Multiplex ligation-dependent probe amplification testing was further carried out among those patients without known disease-causing gene mutations. We simultaneously performed a retrospective study on the reported patients exhibiting HSP in other Chinese cohorts. All clinical and molecular characterization from above two groups of Chinese HSP patients were analyzed and summarized. Eventually, we further validated the cellular changes in fibroblasts of two major spastic paraplegia (SPG) patients (SPG4 and SPG11) in vitro. RESULTS: Most patients of ADHSP (94%) are pure forms, whereas most patients of ARHSP (78%) tend to be complicated forms. In ADHSP, we found that SPG4 (79%) was the most prevalent, followed by SPG3A (11%), SPG6 (4%) and SPG33 (2%). Subtle mutations were the common genetic cause for SPG4 patients and most of them located in AAA cassette domain of spastin protein. In ARHSP, the most common subtype was SPG11 (53%), followed by SPG5 (32%), SPG35 (6%) and SPG46 (3%). Moreover, haplotype analysis showed a unique haplotype was shared in 14 families carrying c.334C > T (p.R112(*)) mutation in CYP7B1 gene, suggesting the founder effect. Functionally, we observed significantly different patterns of mitochondrial dynamics and network, decreased mitochondrial membrane potential (Δψm), increased reactive oxygen species and reduced ATP content in SPG4 fibroblasts. Moreover, we also found the enlargement of LAMP1-positive organelles and abnormal accumulation of autolysosomes in SPG11 fibroblasts. CONCLUSIONS: Our study present a comprehensive clinical spectrum and genetic landscape for HSP in China. We have also provided additional evidences for mitochondrial and autolysosomal-mediated pathways in the pathogenesis of HSP. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13024-018-0269-1) contains supplementary material, which is available to authorized users. BioMed Central 2018-07-06 /pmc/articles/PMC6035405/ /pubmed/29980238 http://dx.doi.org/10.1186/s13024-018-0269-1 Text en © The Author(s). 2018 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 Article Dong, En-Lin Wang, Chong Wu, Shuang Lu, Ying-Qian Lin, Xiao-Hong Su, Hui-Zhen Zhao, Miao He, Jin Ma, Li-Xiang Wang, Ning Chen, Wan-Jin Lin, Xiang Clinical spectrum and genetic landscape for hereditary spastic paraplegias in China |
title | Clinical spectrum and genetic landscape for hereditary spastic paraplegias in China |
title_full | Clinical spectrum and genetic landscape for hereditary spastic paraplegias in China |
title_fullStr | Clinical spectrum and genetic landscape for hereditary spastic paraplegias in China |
title_full_unstemmed | Clinical spectrum and genetic landscape for hereditary spastic paraplegias in China |
title_short | Clinical spectrum and genetic landscape for hereditary spastic paraplegias in China |
title_sort | clinical spectrum and genetic landscape for hereditary spastic paraplegias in china |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6035405/ https://www.ncbi.nlm.nih.gov/pubmed/29980238 http://dx.doi.org/10.1186/s13024-018-0269-1 |
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