Microdeletion in distal PLP1 enhancers causes hereditary spastic paraplegia 2
Abstract Objectives Hereditary spastic paraplegia (HSP) is a genetically heterogeneous disease caused by over 70 genes, with a significant number of patients still genetically unsolved. In this study, we recruited a suspected HSP family characterized by spasticity, developmental delay, ataxia and hy...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2023-09-01
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| Series: | Annals of Clinical and Translational Neurology |
| Online Access: | https://doi.org/10.1002/acn3.51848 |
| _version_ | 1797684997912526848 |
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| author | Xun Zhou Yige Wang Runcheng He Zhenhua Liu Qian Xu Jifeng Guo Xinxiang Yan Jinchen Li Beisha Tang Sheng Zeng Qiying Sun |
| author_facet | Xun Zhou Yige Wang Runcheng He Zhenhua Liu Qian Xu Jifeng Guo Xinxiang Yan Jinchen Li Beisha Tang Sheng Zeng Qiying Sun |
| author_sort | Xun Zhou |
| collection | DOAJ |
| description | Abstract Objectives Hereditary spastic paraplegia (HSP) is a genetically heterogeneous disease caused by over 70 genes, with a significant number of patients still genetically unsolved. In this study, we recruited a suspected HSP family characterized by spasticity, developmental delay, ataxia and hypomyelination, and intended to reveal its molecular etiology by whole exome sequencing (WES) and long‐read sequencing (LRS) analyses. Methods WES was performed on 13 individuals of the family to identify the causative mutations, including analyses of SNVs (single‐nucleotide variants) and CNVs (copy number variants). Accurate circular consensus (CCS) long‐read sequencing (LRS) was used to verify the findings of CNV analysis from WES. Results SNVs analysis identified a missense variant c.195G>T (p.E65D) of MORF4L2 at Xq22.2 co‐segregating in this family from WES data. Further CNVs analysis revealed a microdeletion, which was adjacent to the MORF4L2 gene, also co‐segregating in this family. LRS verified this microdeletion and confirmed the deletion range (chrX: 103,690,507–103,715,018, hg38) with high resolution at nucleotide level accuracy. Interpretations In this study, we identified an Xq22.2 microdeletion (about 24.5 kb), which contains distal enhancers of the PLP1 gene, as a likely cause of SPG2 in this family. The lack of distal enhancers may result in transcriptional repression of PLP1 in oligodendrocytes, potentially affecting its role in the maintenance of myelin, and causing SPG2 phenotype. This study has highlighted the importance of noncoding genomic alterations in the genetic etiology of SPG2. |
| first_indexed | 2024-03-12T00:38:55Z |
| format | Article |
| id | doaj.art-2c486fe180f04ea1b1d10d2dc6d4176d |
| institution | Directory Open Access Journal |
| issn | 2328-9503 |
| language | English |
| last_indexed | 2024-03-12T00:38:55Z |
| publishDate | 2023-09-01 |
| publisher | Wiley |
| record_format | Article |
| series | Annals of Clinical and Translational Neurology |
| spelling | doaj.art-2c486fe180f04ea1b1d10d2dc6d4176d2023-09-15T09:08:30ZengWileyAnnals of Clinical and Translational Neurology2328-95032023-09-011091590160210.1002/acn3.51848Microdeletion in distal PLP1 enhancers causes hereditary spastic paraplegia 2Xun Zhou0Yige Wang1Runcheng He2Zhenhua Liu3Qian Xu4Jifeng Guo5Xinxiang Yan6Jinchen Li7Beisha Tang8Sheng Zeng9Qiying Sun10Department of Geriatric Neurology, Xiangya Hospital Central South University Changsha ChinaDepartment of Neurology, Xiangya Hospital Central South University Changsha ChinaDepartment of Neurology, Xiangya Hospital Central South University Changsha ChinaDepartment of Neurology, Xiangya Hospital Central South University Changsha ChinaDepartment of Neurology, Xiangya Hospital Central South University Changsha ChinaDepartment of Neurology, Xiangya Hospital Central South University Changsha ChinaDepartment of Neurology, Xiangya Hospital Central South University Changsha ChinaDepartment of Geriatric Neurology, Xiangya Hospital Central South University Changsha ChinaDepartment of Geriatric Neurology, Xiangya Hospital Central South University Changsha ChinaDepartment of Geriatrics, The Second Xiangya Hospital Central South University Changsha ChinaDepartment of Geriatric Neurology, Xiangya Hospital Central South University Changsha ChinaAbstract Objectives Hereditary spastic paraplegia (HSP) is a genetically heterogeneous disease caused by over 70 genes, with a significant number of patients still genetically unsolved. In this study, we recruited a suspected HSP family characterized by spasticity, developmental delay, ataxia and hypomyelination, and intended to reveal its molecular etiology by whole exome sequencing (WES) and long‐read sequencing (LRS) analyses. Methods WES was performed on 13 individuals of the family to identify the causative mutations, including analyses of SNVs (single‐nucleotide variants) and CNVs (copy number variants). Accurate circular consensus (CCS) long‐read sequencing (LRS) was used to verify the findings of CNV analysis from WES. Results SNVs analysis identified a missense variant c.195G>T (p.E65D) of MORF4L2 at Xq22.2 co‐segregating in this family from WES data. Further CNVs analysis revealed a microdeletion, which was adjacent to the MORF4L2 gene, also co‐segregating in this family. LRS verified this microdeletion and confirmed the deletion range (chrX: 103,690,507–103,715,018, hg38) with high resolution at nucleotide level accuracy. Interpretations In this study, we identified an Xq22.2 microdeletion (about 24.5 kb), which contains distal enhancers of the PLP1 gene, as a likely cause of SPG2 in this family. The lack of distal enhancers may result in transcriptional repression of PLP1 in oligodendrocytes, potentially affecting its role in the maintenance of myelin, and causing SPG2 phenotype. This study has highlighted the importance of noncoding genomic alterations in the genetic etiology of SPG2.https://doi.org/10.1002/acn3.51848 |
| spellingShingle | Xun Zhou Yige Wang Runcheng He Zhenhua Liu Qian Xu Jifeng Guo Xinxiang Yan Jinchen Li Beisha Tang Sheng Zeng Qiying Sun Microdeletion in distal PLP1 enhancers causes hereditary spastic paraplegia 2 Annals of Clinical and Translational Neurology |
| title | Microdeletion in distal PLP1 enhancers causes hereditary spastic paraplegia 2 |
| title_full | Microdeletion in distal PLP1 enhancers causes hereditary spastic paraplegia 2 |
| title_fullStr | Microdeletion in distal PLP1 enhancers causes hereditary spastic paraplegia 2 |
| title_full_unstemmed | Microdeletion in distal PLP1 enhancers causes hereditary spastic paraplegia 2 |
| title_short | Microdeletion in distal PLP1 enhancers causes hereditary spastic paraplegia 2 |
| title_sort | microdeletion in distal plp1 enhancers causes hereditary spastic paraplegia 2 |
| url | https://doi.org/10.1002/acn3.51848 |
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