Abstract

Congenital disorders of glycosylation (CDG) include 150 disorders constituting in genetically and clinically heterogeneous diseases, showing significant glycoprotein hypoglycosylation that leads to pathological consequences on multiple organs and systems which underlying mechanisms are not yet understood. A few cellular and animal models have been used to study specific CDG characteristics although they have given limited information due to the few CDG mutations tested and the still missing comprehensive molecular and cellular basic research. Here we provide specific gene expression profiles, based on RNA microarray analysis, together with some biochemical and cellular characteristics of a total of 9 control EBV-transformed lymphoblastoid B cell lines (B-LCL) and 13 CDG B-LCL from patients carrying severe mutations in the PMM2 gene, strong serum protein hypoglycosylation and neurological symptoms. Significantly dysregulated genes in PMM2-CDG cells included those regulating stress responses, transcription factors, glycosylation, motility, cell junction and, importantly, those related to development and neuronal differentiation and synapse such as CA2 and ADAM23. PMM2-CDG associated biological consequences involved the unfolded protein response, RNA metabolism and the endoplasmic reticulum, Golgi apparatus and mitochondria components. Changes in transcriptional and CA2 protein levels are consistent with CDG physiopathology. These results demonstrate the global transcriptional impact in phosphomannomutase 2 deficient cells, reveal CA2 as a potential cellular biomarker and confirm B-LCL as an advantageous model for CDG studies.

中文翻译：

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剖析磷酸甘露糖酶 2 缺陷细胞的转录程序：B-LCL 作为先天性糖基化疾病研究的有价值模型

摘要

先天性糖基化疾病 (CDG) 包括 150 种由遗传和临床异质性疾病构成的疾病，显示出显着的糖蛋白低糖基化，导致对多个器官和系统的病理后果，其潜在机制尚不清楚。一些细胞和动物模型已被用于研究特定的 CDG 特征，尽管由于测试的 CDG 突变很少并且仍然缺少全面的分子和细胞基础研究，它们提供的信息有限。在这里，我们提供了基于 RNA 微阵列分析的特定基因表达谱，以及来自携带严重突变的患者的总共 9 个对照 EBV 转化的淋巴母细胞 B 细胞系 (B-LCL) 和 13 个 CDG B-LCL 的一些生化和细胞特征在里面PMM2基因、强血清蛋白低糖基化和神经系统症状。PMM2-CDG 细胞中显着失调的基因包括那些调节应激反应、转录因子、糖基化、运动性、细胞连接的基因，重要的是，那些与发育和神经元分化和突触相关的基因，如 CA2 和 ADAM23。PMM2-CDG 相关的生物学后果涉及未折叠蛋白反应、RNA 代谢和内质网、高尔基体和线粒体成分。转录和 CA2 蛋白水平的变化与 CDG 病理生理学一致。这些结果证明了磷酸甘露聚糖酶 2 缺陷细胞的整体转录影响，揭示了 CA2 作为潜在的细胞生物标志物，并确认 B-LCL 是 CDG 研究的有利模型。