Mutations in COG2 encoding a subunit of the conserved oligomeric golgi complex cause a congenital disorder of glycosylation
Mutations in COG2 encoding a subunit of the conserved oligomeric golgi complex cause a congenital disorder of glycosylation
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DOI：
10.1111/cge.12417
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发表时间：
2015-05-01
影响因子：
3.5
通讯作者：
Saitsu, H.
中科院分区：
文献类型：
--
作者：
Kodera, H.;Ando, N.;Saitsu, H.
保守的低聚高尔基（COG）复合物参与高尔基逆行运输，在先天性糖基化疾病（CDG）中报道了其8个亚基中的6个突变。我们在此报告一位表现出严重的获得性小头畸形、精神运动迟缓、癫痫、肝功能障碍、低铜血症和低铜纤溶酶血症的患者。他的血清糖蛋白分析显示糖末端的唾液化和半乳糖基化都有缺陷。三基全外显子组测序鉴定出COG2中的两个杂合突变：一个新移码突变[c]。701dup (p.Tyr234*)]和错义突变[c]。1900 t > G (p.Trp634Gly)]。克隆的逆转录聚合酶链反应（RT-PCR）产物测序显示，这两个突变都位于不同的等位基因上，正如预期的那样，携带移码突变的突变转录物经历了降解。c.1900T >g （p.Trp634Gly）突变位于脊椎动物中高度保守的结构域，在公共数据库和对照外显子组中都不存在。COG2以及COG3和COG4的蛋白表达在患者的成纤维细胞中降低。我们的数据强烈表明，这些COG2的复合杂合突变是CDG的病因。
The conserved oligomeric Golgi (COG) complex is involved in intra-Golgi retrograde trafficking, and mutations in six of its eight subunits have been reported in congenital disorders of glycosylation (CDG). Here we report a patient showing severe acquired microcephaly, psychomotor retardation, seizures, liver dysfunction, hypocupremia, and hypoceruloplasminemia. Analysis of his serum glycoproteins revealed defects in both sialylation and galactosylation of glycan termini. Trio-based whole-exome sequencing identified two heterozygous mutations in COG2: a de novo frameshift mutation [c.701dup (p.Tyr234*)] and a missense mutation [c.1900T>G (p.Trp634Gly)]. Sequencing of cloned reverse-transcription polymerase chain reaction (RT-PCR) products revealed that both mutations were located on separate alleles, as expected, and that the mutant transcript harboring the frameshift mutation underwent degradation. The c.1900T>G (p.Trp634Gly) mutation is located in a domain highly conserved among vertebrates and was absent from both the public database and our control exomes. Protein expression of COG2, along with COG3 and COG4, was decreased in fibroblasts from the patient. Our data strongly suggest that these compound heterozygous mutations in COG2 are causative of CDG.