A missense variant in the SOX5 gene (c.221C > T) is associated with intellectual disability
Abstract Objectives The SOX5 gene has been identified as the pathogenic gene responsible for Lamb-Shaffer syndrome. In this study, we examined the SOX5 variant (c.221C > T, p.Thr74Met) within a Chinese family presenting with intellectual disability and evaluated the functional implications of SOX...
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| Format: | Article |
| Language: | English |
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BMC
2025-02-01
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| Series: | Orphanet Journal of Rare Diseases |
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| Online Access: | https://doi.org/10.1186/s13023-025-03548-z |
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| author | Xiujuan Yang Zhongzhi Gan Xiaoling Guo Xiang Huang Juan Liu Yingchun Zheng Xiaoqiang Zhou Jingli Lian Yue Liu Tingting Yang Chao Li Fenying Chen Fei He Xiangmin Xu Yasi Zhou Qian Liu Xingkun Yang Fu Xiong |
| author_facet | Xiujuan Yang Zhongzhi Gan Xiaoling Guo Xiang Huang Juan Liu Yingchun Zheng Xiaoqiang Zhou Jingli Lian Yue Liu Tingting Yang Chao Li Fenying Chen Fei He Xiangmin Xu Yasi Zhou Qian Liu Xingkun Yang Fu Xiong |
| author_sort | Xiujuan Yang |
| collection | DOAJ |
| description | Abstract Objectives The SOX5 gene has been identified as the pathogenic gene responsible for Lamb-Shaffer syndrome. In this study, we examined the SOX5 variant (c.221C > T, p.Thr74Met) within a Chinese family presenting with intellectual disability and evaluated the functional implications of SOX5 by in vitro experiment. Materials and methods The family underwent a clinical assessment of intellectual development, which included precise clinical exome sequencing to identify causative genetic variants. The potential deleterious effects and pathogenicity of the variant were predicted using bioinformatics tools such as Mutation Taster, PROVEAN, and SIFT. Additionally, protein stability was evaluated using I-Mutant, and 3D protein structures were modeled with I-TASSER. Western blots and QPCR were employed to assess gene expression and protein stability. Flow cytometry was utilized to compare the cell cycle dynamics between wild-type and mutant cells. Results A previously identified missense variant (c.221C > T) in the SOX5 gene was determined to be the underlying cause of intellectual disability in a Chinese family. Functional assays demonstrated that mutant cells exhibited increased levels of SOX5 mRNA and protein relative to wild-type cells, accompanied by enhanced protein stability. Additionally, the mutant SOX5 protein was found to alter the cell cycle and downregulate the mRNA expression levels of the ACAN, AXIN2, SOX9, and PDGFRA genes. Conclusions We confirmed that the SOX5 p.Thr74Met variant is associated with intellectual disability in a second-generation Chinese family. This mutant protein potentially exhibits increased stability, influences the cell cycle, and downregulates genes related to bone and neural functions. |
| format | Article |
| id | doaj-art-eab35b4ce4fe419d85f7e2ea0359a756 |
| institution | Kabale University |
| issn | 1750-1172 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Orphanet Journal of Rare Diseases |
| spelling | doaj-art-eab35b4ce4fe419d85f7e2ea0359a7562025-02-09T12:54:00ZengBMCOrphanet Journal of Rare Diseases1750-11722025-02-0120111210.1186/s13023-025-03548-zA missense variant in the SOX5 gene (c.221C > T) is associated with intellectual disabilityXiujuan Yang0Zhongzhi Gan1Xiaoling Guo2Xiang Huang3Juan Liu4Yingchun Zheng5Xiaoqiang Zhou6Jingli Lian7Yue Liu8Tingting Yang9Chao Li10Fenying Chen11Fei He12Xiangmin Xu13Yasi Zhou14Qian Liu15Xingkun Yang16Fu Xiong17The Affiliated Foshan Women and Children Hospital, Guangdong Medical UniversityDepartment of Medical Genetics/Experimental Education/Administration Center, School of Basic Medical Sciences, Southern Medical UniversityThe Affiliated Foshan Women and Children Hospital, Guangdong Medical UniversityThe Affiliated Foshan Women and Children Hospital, Guangdong Medical UniversityThe Affiliated Foshan Women and Children Hospital, Guangdong Medical UniversityDepartment of Medical Genetics/Experimental Education/Administration Center, School of Basic Medical Sciences, Southern Medical UniversityThe Affiliated Foshan Women and Children Hospital, Guangdong Medical UniversityThe Affiliated Foshan Women and Children Hospital, Guangdong Medical UniversityThe Affiliated Foshan Women and Children Hospital, Guangdong Medical UniversityThe Affiliated Foshan Women and Children Hospital, Guangdong Medical UniversityThe Affiliated Foshan Women and Children Hospital, Guangdong Medical UniversityThe Affiliated Foshan Women and Children Hospital, Guangdong Medical UniversityDepartment of Medical Genetics/Experimental Education/Administration Center, School of Basic Medical Sciences, Southern Medical UniversityClinical Research Center of Scientific Research Division, Nanfang Hospital, Southern Medical UniversityFoshan Pulisheng BiotechnologyThe First Clinical Medical School, Nan Fang Hospital, Southern Medical UniversityThe Affiliated Foshan Women and Children Hospital, Guangdong Medical UniversityDepartment of Medical Genetics/Experimental Education/Administration Center, School of Basic Medical Sciences, Southern Medical UniversityAbstract Objectives The SOX5 gene has been identified as the pathogenic gene responsible for Lamb-Shaffer syndrome. In this study, we examined the SOX5 variant (c.221C > T, p.Thr74Met) within a Chinese family presenting with intellectual disability and evaluated the functional implications of SOX5 by in vitro experiment. Materials and methods The family underwent a clinical assessment of intellectual development, which included precise clinical exome sequencing to identify causative genetic variants. The potential deleterious effects and pathogenicity of the variant were predicted using bioinformatics tools such as Mutation Taster, PROVEAN, and SIFT. Additionally, protein stability was evaluated using I-Mutant, and 3D protein structures were modeled with I-TASSER. Western blots and QPCR were employed to assess gene expression and protein stability. Flow cytometry was utilized to compare the cell cycle dynamics between wild-type and mutant cells. Results A previously identified missense variant (c.221C > T) in the SOX5 gene was determined to be the underlying cause of intellectual disability in a Chinese family. Functional assays demonstrated that mutant cells exhibited increased levels of SOX5 mRNA and protein relative to wild-type cells, accompanied by enhanced protein stability. Additionally, the mutant SOX5 protein was found to alter the cell cycle and downregulate the mRNA expression levels of the ACAN, AXIN2, SOX9, and PDGFRA genes. Conclusions We confirmed that the SOX5 p.Thr74Met variant is associated with intellectual disability in a second-generation Chinese family. This mutant protein potentially exhibits increased stability, influences the cell cycle, and downregulates genes related to bone and neural functions.https://doi.org/10.1186/s13023-025-03548-zIntellectual disabilitySOX5C.221C > TBioinformatics predictionProtein stabilityDown-regulate |
| spellingShingle | Xiujuan Yang Zhongzhi Gan Xiaoling Guo Xiang Huang Juan Liu Yingchun Zheng Xiaoqiang Zhou Jingli Lian Yue Liu Tingting Yang Chao Li Fenying Chen Fei He Xiangmin Xu Yasi Zhou Qian Liu Xingkun Yang Fu Xiong A missense variant in the SOX5 gene (c.221C > T) is associated with intellectual disability Orphanet Journal of Rare Diseases Intellectual disability SOX5 C.221C > T Bioinformatics prediction Protein stability Down-regulate |
| title | A missense variant in the SOX5 gene (c.221C > T) is associated with intellectual disability |
| title_full | A missense variant in the SOX5 gene (c.221C > T) is associated with intellectual disability |
| title_fullStr | A missense variant in the SOX5 gene (c.221C > T) is associated with intellectual disability |
| title_full_unstemmed | A missense variant in the SOX5 gene (c.221C > T) is associated with intellectual disability |
| title_short | A missense variant in the SOX5 gene (c.221C > T) is associated with intellectual disability |
| title_sort | missense variant in the sox5 gene c 221c t is associated with intellectual disability |
| topic | Intellectual disability SOX5 C.221C > T Bioinformatics prediction Protein stability Down-regulate |
| url | https://doi.org/10.1186/s13023-025-03548-z |
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