Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
G3 (Bethesda). 2024 Mar 6;14(3). doi: 10.1093/g3journal/jkad291.
Mutations in the phosphatidylinositol glycan biosynthesis class A (PIGA) gene cause a rare, X-linked recessive congenital disorder of glycosylation. Phosphatidylinositol glycan biosynthesis class A congenital disorder of glycosylation (PIGA-CDG) is characterized by seizures, intellectual and developmental delay, and congenital malformations. The PIGA gene encodes an enzyme involved in the first step of glycosylphosphatidylinositol (GPI) anchor biosynthesis. There are over 100 GPI-anchored proteins that attach to the cell surface and are involved in cell signaling, immunity, and adhesion. Little is known about the pathophysiology of PIGA-CDG. Here, we describe the first Drosophila model of PIGA-CDG and demonstrate that loss of PIG-A function in Drosophila accurately models the human disease. As expected, complete loss of PIG-A function is larval lethal. Heterozygous null animals appear healthy but, when challenged, have a seizure phenotype similar to what is observed in patients. To identify the cell-type specific contributions to disease, we generated neuron- and glia-specific knockdown of PIG-A. Neuron-specific knockdown resulted in reduced lifespan and a number of neurological phenotypes but no seizure phenotype. Glia-knockdown also reduced lifespan and, notably, resulted in a very strong seizure phenotype. RNA sequencing analyses demonstrated that there are fundamentally different molecular processes that are disrupted when PIG-A function is eliminated in different cell types. In particular, loss of PIG-A in neurons resulted in upregulation of glycolysis, but loss of PIG-A in glia resulted in upregulation of protein translation machinery. Here, we demonstrate that Drosophila is a good model of PIGA-CDG and provide new data resources for future study of PIGA-CDG and other GPI anchor disorders.
突变磷脂酰肌醇聚糖生物合成 A 类（PIGA）基因导致一种罕见的 X 连锁隐性先天性糖基化障碍。磷脂酰肌醇聚糖生物合成 A 先天性糖基化障碍（PIGA-CDG）的特征是癫痫发作、智力和发育迟缓以及先天性畸形。PIGA 基因编码一种参与糖基磷脂酰肌醇（GPI）锚生物合成第一步的酶。有超过 100 种 GPI 锚定蛋白附着在细胞表面，参与细胞信号转导、免疫和黏附。关于 PIGA-CDG 的病理生理学知之甚少。在这里，我们描述了第一个 PIGA-CDG 的果蝇模型，并证明了果蝇中 PIG-A 功能的丧失准确地模拟了人类疾病。正如预期的那样，完全丧失 PIG-A 功能是幼虫致死的。杂合子缺失动物看起来健康，但受到挑战时，会出现类似于患者观察到的癫痫发作表型。为了确定对疾病的细胞类型特异性贡献，我们生成了神经元和神经胶质特异性的 PIG-A 敲低。神经元特异性敲低导致寿命缩短和许多神经表型，但没有癫痫发作表型。神经胶质敲低也降低了寿命，值得注意的是，导致了非常强烈的癫痫发作表型。RNA 测序分析表明，当 PIG-A 功能在不同细胞类型中被消除时，存在根本不同的被破坏的分子过程。特别是，神经元中 PIG-A 的缺失导致糖酵解的上调，但神经胶质中 PIG-A 的缺失导致蛋白质翻译机制的上调。在这里，我们证明了果蝇是 PIGA-CDG 的良好模型，并为 PIGA-CDG 和其他 GPI 锚定障碍的进一步研究提供了新的数据资源。
