Fatal outcome due to deficiency of subunit 6 of the conserved oligomeric Golgi complex leading to a new type of congenital disorders of glycosylation
Fatal outcome due to deficiency of subunit 6 of the conserved oligomeric Golgi complex leading to a new type of congenital disorders of glycosylation
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DOI：
10.1093/hmg/ddq278
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发表时间：
2010-09-15
影响因子：
3.5
通讯作者：
Koerner, Christian
中科院分区：
文献类型：
--
作者：
Luebbehusen, Juergen;Thiel, Christian;Koerner, Christian
保守寡聚高尔基体 (COG6) 复合体的亚基 6 缺陷导致先天性糖基化疾病的新的 N- 和 O- 糖基化联合缺陷，称为 CDG-IIL (COG6-CDG)。指标患者患有严重的神经系统疾病，其特征是维生素 K 缺乏、呕吐、顽固性局灶性癫痫发作、颅内出血和婴儿早期致命的结果。通过 HPLC 和质谱分析血清转铁蛋白中的寡糖，发现半乳糖和唾液酸残基丢失，而这些糖残基分别输入和转移到富含高尔基体的囊泡或蛋白质上的情况正常或略有减少。蛋白质印迹检查与凝胶过滤色谱研究相结合，在患者来源的皮肤成纤维细胞中显示，上述亚基的表达严重降低，并且以完整的 COG 复合物为代价，出现了 COG 复合物片段。 COG6-cDNA和COG6基因的测序导致纯合突变(c.G1646T)，导致COG6蛋白中的氨基酸交换p.G549V。免疫荧光分析证明，在布雷菲德菌素 A 治疗后，患者成纤维细胞与野生型 COG6-cDNA 的逆转录病毒互补导致 COG 复合物依赖性逆行蛋白转运正常化。
Deficiency of subunit 6 of the conserved oligomeric Golgi (COG6) complex causes a new combined N- and O-glycosylation deficiency of the congenital disorders of glycosylation, designated as CDG-IIL (COG6-CDG). The index patient presented with a severe neurologic disease characterized by vitamin K deficiency, vomiting, intractable focal seizures, intracranial bleedings and fatal outcome in early infancy. Analysis of oligosaccharides from serum transferrin by HPLC and mass spectrometry revealed the loss of galactose and sialic acid residues, whereas import and transfer of these sugar residues into Golgi-enriched vesicles or onto proteins, respectively, were normal to slightly reduced. Western blot examinations combined with gel filtration chromatography studies in patient-derived skin fibroblasts showed a severely reduced expression of the mentioned subunit and the occurrence of COG complex fragments at the expense of the integral COG complex. Sequencing of COG6-cDNA and COG6 gene resulted in a homozygous mutation (c.G1646T), leading to amino acid exchange p.G549V in the COG6 protein. Retroviral complementation of the patients' fibroblasts with the wild-type COG6-cDNA led to normalization of the COG complex-depending retrograde protein transport after Brefeldin A treatment, demonstrated by immunofluorescence analysis.