Department of Pediatrics, University Hospital of Muenster, Muenster, Germany.
Department of Paediatrics, Olgahospital, Stuttgart, Germany.
Am J Med Genet A. 2019 Jul;179(7):1371-1375. doi: 10.1002/ajmg.a.61190. Epub 2019 May 10.
Accurate glycosylation of proteins is essential for their function and their intracellular transport. Numerous diseases have been described, where either glycosylation or intracellular transport of proteins is impaired. Coat protein I (COPI) is involved in anterograde and retrograde transport of proteins between endoplasmic reticulum and Golgi, where glycosylation takes place, but no association of defective COPI proteins and glycosylation defects has been described so far. We identified a patient whose phenotype at a first glance was reminiscent of PGM1 deficiency, a disease that also affects N-glycosylation of proteins. More detailed analyses revealed a different disease with a glycosylation deficiency that was only detectable during episodes of acute illness of the patient. Trio-exome analysis revealed a de novo loss-of-function mutation in ARCN1, coding for the delta-COP subunit of COPI. We hypothesize that the capacity of flow through Golgi is reduced by this defect and at high protein synthesis rates, this bottleneck also manifests as transient glycosylation deficiency.
蛋白质的糖基化精确性对于其功能和细胞内运输至关重要。许多疾病已经被描述，其中蛋白质的糖基化或细胞内运输受到损害。衣壳蛋白 I（COPI）参与内质网和高尔基体之间的蛋白质正向和逆向运输，在那里发生糖基化，但目前尚未描述 COPI 蛋白缺陷和糖基化缺陷的关联。我们鉴定了一名患者，其表型乍一看让人联想到 PGM1 缺乏症，这也是一种影响蛋白质 N-糖基化的疾病。更详细的分析显示出一种不同的疾病，其糖基化缺陷仅在患者急性疾病发作期间才可检测到。三人外显子组分析显示 ARCN1 发生新生致病变异，该基因编码 COPI 的 δ-COP 亚基。我们假设该缺陷降低了高尔基体的通透性，并且在高蛋白质合成速率下，这个瓶颈也表现为短暂的糖基化缺陷。
