新致病基因TMEM63A突变影响少突胶质细胞钙离子内流导致髓鞘形成低下的机制研究

髓鞘形成低下性脑白质营养不良（HLD）的临床特征为脑白质髓鞘化低下，共19型，本团队主导定位的新致病基因TMEM63A导致的HLD19具有独特的发育相关临床特征，拟通过以下研究来阐明其发生机制：①在转染TMEM63A突变体的人类少突胶质细胞系上观察TMEM63A表达、钙离子信号以及细胞器互作网络稳态的改变；②在患者来源的TMEM63A c.503G>A突变诱导多功能干细胞诱导的类脑体模型上研究不同发育期少突胶质细胞分化与增殖、髓鞘形成以及转录组学的变化；③在Tmem63a c.500G>A敲入大鼠模型上观察TMEM63A突变蛋白在大脑不同发育阶段脑区的表达、髓鞘病理学以及行为认知的改变。通过以上三个层面研究内容的实施将阐明TMEM63A突变导致髓鞘形成低下可能的细胞与分子机制，解释TMEM63A突变导致的HLD19独特临床表型，为HLD及类似疾病的共同发生机制提供线索资料。

Hypomyelination leukodystrophy (HLD) includes 19 subtypes and is characterized by myelin deficit. Mutations in TMEM63A, a novel disease-causing gene that our team identified, lead to HLD19 with unique clinical features related to development. To elucidate the underlying mechanism, experiments will be conducted as follows: ①expression of TMEM63A, signal of calcium, and homeostasis of organelle interaction network will be measured in human oligodendrocyte lines transfected with TMEM63A mutants; ②differentiation and proliferation of oligodendrocytes, myelination and transcriptome in different developmental stages will be analyzed in brain organoids constructed based on induced pluripotent stem cells that are derived from patients with TMEM63A c.503G>A mutation; ③expression of TMEM63A in different areas of brain, myelin pathology and motor and cognitive ability in developmental stages will be observed in Tmem63a c.500G>A knock-in rat model. Through above experiments in three levels, we try to elucidate the possible cellular and molecular mechanisms of hypomyelination and unique clinical features of HLD19 caused by TMEM63A mutations. The study will provide clues to common mechanism of HLD and similar diseases.