A new inborn error of glycosylation due to a Cog8 deficiency reveals a critical role for the Cog1-Cog8 interaction in COG complex formation
A new inborn error of glycosylation due to a Cog8 deficiency reveals a critical role for the Cog1-Cog8 interaction in COG complex formation
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DOI：
10.1093/hmg/ddl476
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发表时间：
2007-04-01
影响因子：
3.5
通讯作者：
Matthijs, Gert
中科院分区：
文献类型：
--
作者：
Foulquier, Francois;Ungar, Daniel;Matthijs, Gert
异质八聚体保守低聚高尔基（COG）复合物通过调节膜运输对高尔基体的结构/功能至关重要。在这里，我们描述了一个轻度形式的先天性糖基化II型疾病（CDG-II）的患者，这是由hCOG8基因的纯合无义突变引起的。这导致过早终止密码子，导致co8亚基截断，缺乏76个c端氨基酸。质谱分析发现N-和o -聚糖结构有轻微的唾液化缺陷。我们发现这种N-和o -糖基化缺陷的分子基础是由于截断导致Cog1-Cog8相互作用的破坏。因此，Cog1缺乏伴随着Cog8缺乏，阻碍了完整、稳定复合物的组装，导致更小亚复合物的出现。此外，β 1,4-半乳糖转移酶水平显著降低。用全长co8转染患者成纤维细胞可完全恢复o -糖基化缺陷。本文描述的Cog8缺陷代表了一种新型的CDG- ii，我们建议将其命名为CDG- iih或由Cog8缺陷引起的CDG （CDG- ii /Cog8）。
The hetero-octameric conserved oligomeric Golgi (COG) complex is essential for the structure/function of the Golgi apparatus through regulation of membrane trafficking. Here, we describe a patient with a mild form of a congenital disorder of glycosylation type II (CDG-II), which is caused by a homozygous nonsense mutation in the hCOG8 gene. This leads to a premature stop codon resulting in a truncated Cog8 subunit lacking the 76 C-terminal amino acids. Mass spectrometric analysis of the N- and O-glycan structures identified a mild sialylation deficiency. We showed that the molecular basis of this defect in N- and O-glycosylation is caused by the disruption of the Cog1-Cog8 interaction due to truncation. As a result, Cog1 deficiency accompanies the Cog8 deficiency, preventing assembly of the intact, stable complex and resulting in the appearance of smaller subcomplexes. Moreover, levels of beta 1,4-galactosytransferase were significantly reduced. The defects in O-glycosylation could be fully restored by transfecting the patient's fibroblasts with full-length Cog8. The Cog8 defect described here represents a novel type of CDG-II, which we propose to name as CDG-IIh or CDG caused by Cog8 deficiency (CDG-II/Cog8).