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<p>Accurate timing of myelination is crucial for the proper functioning of the central nervous system. Here, we identified a <i>de novo</i> heterozygous mutation in <i>TMEM63A</i> (c.1894G&gt;A; p. Ala632Thr) in a 7-year-old boy exhibiting hypomyelination. A Ca<sup>2+</sup> influx assay suggested that this is a loss-of-function mutation. To explore how TMEM63A deficiency causes hypomyelination, we generated <i>Tmem63a</i> 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 <i>Tmem63a</i><sup>−/−</sup> OPCs presented delayed differentiation. Lentivirus-based expression of TMEM63A but not TMEM63A_A632T rescued the differentiation of <i>Tmem63a</i><sup>−/−</sup> OPCs <i>in vitro</i> and myelination in <i>Tmem63a</i><sup>−/−</sup> 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 Ca<sup>2+</sup> influx plays critical roles in the early development of myelin and oligodendrocyte differentiation.</p>

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Cation Channel TMEM63A Autonomously Facilitates Oligodendrocyte Differentiation at an Early Stage

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月21日

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  • 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

摘要

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.