Center for Medical Genetics, Hunan Key Laboratory of Medical Genetics, MOE KeyLab of Rare Pediatric Diseases, School of Life Sciences, Central South University, Changsha, China.
Department of Medical Genetics, Hunan Jiahui Genetics Hospital, Changsha, China.
Cell Death Dis. 2024 Nov 9;15(11):808. doi: 10.1038/s41419-024-07201-8.
Biallelic mutations in PIGK cause GPI biosynthesis defect 22 (GPIBD22), characterized with developmental delay, hypotonia, and cerebellar atrophy. The understanding of the underlying causes is limited due to the lack of suitable disease models. To address this gap, we generated a mouse model with PIGK deficits, specifically in Purkinje cells (Pcp2-cko) and an induced pluripotent stem cell (iPSC) model using the c.87dupT mutant (KI) found in GPIBD22 patients. Pcp2-cko mice demonstrated cerebellar atrophy, ataxia and progressive Purkinje cells loss which were accompanied by increased apoptosis and neuroinflammation. Similarly, KI iPSCs exhibited increased apoptosis and accelerated neural rosette formation, indicating that PIGK defects could impact early neural differentiation that confirmed by the RNA-Seq results of neural progenitor cells (NPCs). The increased apoptosis and accelerated NPC differentiation in KI iPSCs are associated with excessive unfolded protein response (UPR) pathway activation, and can be rescued by UPR pathway inhibitor. Our study reveals potential pathogenic mechanism of GPIBD22 and providing new insights into the therapeutic strategy for GPIBD.
PIGK 中的双等位基因突变导致糖基磷脂酰肌醇生物合成缺陷 22（GPIBD22），其特征为发育迟缓、肌张力减退和小脑萎缩。由于缺乏合适的疾病模型，对其潜在病因的了解有限。为了解决这一差距，我们生成了一种 PIGK 缺陷的小鼠模型，特别是在浦肯野细胞（Pcp2-cko）中，并使用在 GPIBD22 患者中发现的 c.87dupT 突变（KI）构建了诱导多能干细胞（iPSC）模型。Pcp2-cko 小鼠表现出小脑萎缩、共济失调和进行性浦肯野细胞丢失，伴随着细胞凋亡和神经炎症增加。同样，KI iPSC 表现出细胞凋亡增加和神经玫瑰花结形成加速，表明 PIGK 缺陷可能会影响早期神经分化，这通过神经祖细胞（NPC）的 RNA-Seq 结果得到证实。KI iPSC 中增加的细胞凋亡和加速的 NPC 分化与过度未折叠蛋白反应（UPR）途径激活有关，可通过 UPR 途径抑制剂挽救。我们的研究揭示了 GPIBD22 的潜在发病机制，并为 GPIBD 的治疗策略提供了新的见解。
