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HNRNPH2 variant linked to intellectual disability disrupts myelination by impairing oligodendrocyte differentiation

Yang Jiao,  Xingyu Pan,  Jingrong Zhao,  Xiaoyu Teng,  Xiaoyi Liao,  Xinyu Hu,  Qiu Wang,  Dandan Zheng,  Yuxiang Pan,  Xiaohui Deng,  Xinyi Tan,  Yun Stone Shi,  Xu Zhang,  Lan Bao,  Bin Wang

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文章导航 > Journal of Genetics and Genomics  > 2025 > 优先出版
Yang Jiao, Xingyu Pan, Jingrong Zhao, Xiaoyu Teng, Xiaoyi Liao, Xinyu Hu, Qiu Wang, Dandan Zheng, Yuxiang Pan, Xiaohui Deng, Xinyi Tan, Yun Stone Shi, Xu Zhang, Lan Bao, Bin Wang. HNRNPH2 variant linked to intellectual disability disrupts myelination by impairing oligodendrocyte differentiation[J]. 遗传学报. doi: 10.1016/j.jgg.2025.12.006
引用本文: Yang Jiao, Xingyu Pan, Jingrong Zhao, Xiaoyu Teng, Xiaoyi Liao, Xinyu Hu, Qiu Wang, Dandan Zheng, Yuxiang Pan, Xiaohui Deng, Xinyi Tan, Yun Stone Shi, Xu Zhang, Lan Bao, Bin Wang. HNRNPH2 variant linked to intellectual disability disrupts myelination by impairing oligodendrocyte differentiation[J]. 遗传学报. doi: 10.1016/j.jgg.2025.12.006
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Yang Jiao, Xingyu Pan, Jingrong Zhao, Xiaoyu Teng, Xiaoyi Liao, Xinyu Hu, Qiu Wang, Dandan Zheng, Yuxiang Pan, Xiaohui Deng, Xinyi Tan, Yun Stone Shi, Xu Zhang, Lan Bao, Bin Wang. HNRNPH2 variant linked to intellectual disability disrupts myelination by impairing oligodendrocyte differentiation[J]. Journal of Genetics and Genomics. doi: 10.1016/j.jgg.2025.12.006
Citation: Yang Jiao, Xingyu Pan, Jingrong Zhao, Xiaoyu Teng, Xiaoyi Liao, Xinyu Hu, Qiu Wang, Dandan Zheng, Yuxiang Pan, Xiaohui Deng, Xinyi Tan, Yun Stone Shi, Xu Zhang, Lan Bao, Bin Wang. HNRNPH2 variant linked to intellectual disability disrupts myelination by impairing oligodendrocyte differentiation[J]. Journal of Genetics and Genomics. doi: 10.1016/j.jgg.2025.12.006
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HNRNPH2 variant linked to intellectual disability disrupts myelination by impairing oligodendrocyte differentiation

doi: 10.1016/j.jgg.2025.12.006

  • a. Guangdong Institute of Intelligence Science and Technology, Hengqin, Zhuhai, Guangdong 519031, China;

  • b. Institute of Neuroscience and State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China;

  • c. Key Laboratory of Multi-cell Systems, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China;

  • d. School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China

基金项目: 

We thank Prof. Jingyi Hui (CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences) for insightful guidance, Dr. Zhixiong Liu (Guangdong Institute of Intelligence Science and Technology) for technical assistance in the OPC culture, and the platform for structure and function of neural network in Guangdong Institute of Intelligence Science and Technology for providing technical support. This work was supported by grants from the National Natural Science Foundation of China (32471018, 32070967, and 32070968).

详细信息
    通讯作者:

    Lan Bao,E-mail:baolan@sibcb.ac.cn

    Bin Wang,E-mail:wangbin@gdiist.cn

HNRNPH2 variant linked to intellectual disability disrupts myelination by impairing oligodendrocyte differentiation

  • a. Guangdong Institute of Intelligence Science and Technology, Hengqin, Zhuhai, Guangdong 519031, China;

  • b. Institute of Neuroscience and State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China;

  • c. Key Laboratory of Multi-cell Systems, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China;

  • d. School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China

Funds: 

We thank Prof. Jingyi Hui (CAS Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences) for insightful guidance, Dr. Zhixiong Liu (Guangdong Institute of Intelligence Science and Technology) for technical assistance in the OPC culture, and the platform for structure and function of neural network in Guangdong Institute of Intelligence Science and Technology for providing technical support. This work was supported by grants from the National Natural Science Foundation of China (32471018, 32070967, and 32070968).

    摘要
  • 摘要: Intellectual disability (ID) arises from complex pathogenic mechanisms. Although myelin dysfunction and white matter damage have been implicated, the cellular and molecular mechanisms linking impaired myelination to cognitive deficits remain largely unknown. Here, we identify a de novo heterogeneous nuclear ribonucleoprotein H2 (HNRNPH2) variant, c.638C>T (p.Pro213Leu), in patients with ID. The Hnrnph2P213L knock-in mice display spatial learning deficits, representing a partial phenotypic overlap with HNRNPH2-related neurodevelopmental disorder. Notably, Hnrnph2P213L mice exhibit significant myelination defects, primarily due to the impaired differentiation of oligodendrocyte progenitor cells. Furthermore, the myelin-enhancing drug benztropine rescues myelination, restores myelin-related gene expression, and ameliorates cognitive deficits, highlighting the role of hnRNPH2 P213L-induced myelin abnormalities in the pathogenesis of ID. Mechanistically, the P213L mutation disrupts the interaction between hnRNPH2 and its target transcripts, leading to the downregulation of myelination-related genes. Collectively, these findings reveal a critical mechanistic connection between myelin dysfunction and ID, thereby offering potential therapeutic insights for X-linked neurodevelopmental disorders.
    Abstract: Intellectual disability (ID) arises from complex pathogenic mechanisms. Although myelin dysfunction and white matter damage have been implicated, the cellular and molecular mechanisms linking impaired myelination to cognitive deficits remain largely unknown. Here, we identify a de novo heterogeneous nuclear ribonucleoprotein H2 (HNRNPH2) variant, c.638C>T (p.Pro213Leu), in patients with ID. The Hnrnph2P213L knock-in mice display spatial learning deficits, representing a partial phenotypic overlap with HNRNPH2-related neurodevelopmental disorder. Notably, Hnrnph2P213L mice exhibit significant myelination defects, primarily due to the impaired differentiation of oligodendrocyte progenitor cells. Furthermore, the myelin-enhancing drug benztropine rescues myelination, restores myelin-related gene expression, and ameliorates cognitive deficits, highlighting the role of hnRNPH2 P213L-induced myelin abnormalities in the pathogenesis of ID. Mechanistically, the P213L mutation disrupts the interaction between hnRNPH2 and its target transcripts, leading to the downregulation of myelination-related genes. Collectively, these findings reveal a critical mechanistic connection between myelin dysfunction and ID, thereby offering potential therapeutic insights for X-linked neurodevelopmental disorders.
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出版历程
  • 收稿日期:  2025-12-02
  • 录用日期:  2025-12-17
  • 修回日期:  2025-12-17
  • 网络出版日期:  2025-12-25

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