Cation Channel TMEM63A Autonomously Facilitates Oligodendrocyte Differentiation at an Early Stage.

Yue-Ying WANG; Dan WU; Yongkun ZHAN; Fei LI; Yan-Yu ZANG; Xiao-Yu TENG; Linlin ZHANG; Gui-Fang DUAN; He WANG; Rong XU; Guiquan CHEN; Yun XU; Jian-Jun YANG; Yongguo YU; Yun Stone SHI

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Cation Channel TMEM63A Autonomously Facilitates Oligodendrocyte Differentiation at an Early Stage.

Author: Yue-Ying WANG ¹ ; Dan WU ¹ ; Yongkun ZHAN ² ; Fei LI ³ ; Yan-Yu ZANG ¹ ; Xiao-Yu TENG ¹ ; Linlin ZHANG ⁴ ; Gui-Fang DUAN ⁵ ; He WANG ⁶ ; Rong XU ⁷ ; Guiquan CHEN ¹ ; Yun XU ¹ ; Jian-Jun YANG ^{8
,

9} ; Yongguo YU ¹⁰ ; Yun Stone SHI ¹¹
Author Information

1. Ministry of Education Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Department of Neurology, Nanjing Drum Tower Hospital, Medical School, Nanjing University, Nanjing, 210032, China.
2. Center of Clinical Genetics, School of Medicine, Xinhua Hospital Affiliated to Shanghai Jiao Tong University , Shanghai, 200092, China.
3. Department of Developmental and Behavioral Pediatrics, Department of Child Primary Care, Brain and Behavioral Research Unit of Shanghai Institute for Pediatric Research and MOE-Shanghai Key Laboratory for Children's Environmental Health, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.
4. Qilu Pharmaceutical Co., Ltd, Jinan, 250100, China.
5. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100091, China.
6. Department of Anesthesiology, Pain and Perioperative Medicine, First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
7. Department of Rehabilitation Medicine, Medical School, Nanjing Drum Tower Hospital, Nanjing University, Nanjing, 210008, China.
8. Department of Anesthesiology, Pain and Perioperative Medicine, First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China. yjyangjj@
9. com.
10. Center of Clinical Genetics, School of Medicine, Xinhua Hospital Affiliated to Shanghai Jiao Tong University , Shanghai, 200092, China. yuyongguo@shsmu.edu.cn.
11. Ministry of Education Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Department of Neurology, Nanjing Drum Tower Hospital, Medical School, Nanjing University, Nanjing, 210032, China. yunshi@nju.edu.cn.
Publication Type:Journal Article
Keywords: Hypomyelination; Mutation; Oligodendrocyte differentiation; TMEM63A
MeSH: Animals; Cell Differentiation/physiology*; Oligodendroglia/metabolism*; Mice, Knockout; Mice; Male; Myelin Sheath/metabolism*; Humans; Child; Cells, Cultured; Oligodendrocyte Precursor Cells/metabolism*
From: Neuroscience Bulletin 2025;41(4):615-632
CountryChina
Language:English
Abstract: Accurate timing of myelination is crucial for the proper functioning of the central nervous system. Here, we identified a de novo heterozygous mutation in TMEM63A (c.1894G>A; p. Ala632Thr) in a 7-year-old boy exhibiting hypomyelination. A Ca²⁺ influx assay suggested that this is a loss-of-function mutation. To explore how TMEM63A deficiency causes hypomyelination, we generated Tmem63a knockout mice. Genetic deletion of TMEM63A resulted in hypomyelination at postnatal day 14 (P14) arising from impaired differentiation of oligodendrocyte precursor cells (OPCs). Notably, the myelin dysplasia was transient, returning to normal levels by P28. Primary cultures of Tmem63a^-/- OPCs presented delayed differentiation. Lentivirus-based expression of TMEM63A but not TMEM63A_A632T rescued the differentiation of Tmem63a^-/- OPCs in vitro and myelination in Tmem63a^-/- mice. These data thus support the conclusion that the mutation in TMEM63A is the pathogenesis of the hypomyelination in the patient. Our study further demonstrated that TMEM63A-mediated Ca²⁺ influx plays critical roles in the early development of myelin and oligodendrocyte differentiation.