Centro de Estudio de las Metabolopatías Congénitas (CEMECO), Hospital de Niños de la Santísima Trinidad, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Ferroviarios 1250, X5014AKN, Córdoba, Argentina.
Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Córdoba, Argentina.
Glycoconj J. 2021 Apr;38(2):191-200. doi: 10.1007/s10719-021-09976-w. Epub 2021 Mar 1.
Human ALG2 encodes an α 1,3mannosyltransferase that catalyzes the first steps in the synthesis of N-glycans in the endoplasmic reticulum. Variants in ALG2cause a congenital disorder of glycosylation (CDG) known as ALG2-CDG. Up to date, nine ALG2-CDG patients have been reported worldwide. ALG2-CDG is a rare autosomal recessive inherited disorder characterized by neurological involvement, convulsive syndrome of unknown origin, axial hypotonia, and mental and motor regression. In this study, we used MALDI-TOF MS to define both total serum protein and transferrin (Tf) N-glycan phenotypes in three ALG2-CDG patients carrying a c.752G > T, p.Arg251Leu ALG2 missense variant in homozygous state, as determined by exome sequencing. Comparing it to control samples, we have observed Tf under-occupancy of glycosylation site(s) typical of a defective N-glycan assembly and the occurrence of oligomannose and hybrid type N-glycans. Moreover, we have observed a slight oligomannose accumulation in total serum glyco-profiles. The increased heterogeneity of serum N-glycome in the studied patients suggests a marginal disarrangement of the glycan processing in ALG2-CDG. Previous studies reported on slightly increased concentrations of abnormal serum N-glycans in CDG-I due to defects in the mannosylation steps of dolichol-linked oligosaccharide biosynthesis. This preliminary work aims at considering serum N-glycan accumulation of high mannosylated glycoforms, such as oligomannose and hybrid type N-glycans, as potential diagnostic signals for ALG2-CDG patients.
人 ALG2 编码一种α1,3-甘露糖基转移酶，该酶催化内质网中 N-聚糖合成的第一步。ALG2 中的变异导致一种称为 ALG2-CDG 的先天性糖基化障碍。迄今为止，全世界已经报道了 9 例 ALG2-CDG 患者。ALG2-CDG 是一种罕见的常染色体隐性遗传性疾病，其特征为神经系统受累、不明原因的惊厥综合征、轴性张力减退以及精神和运动倒退。在这项研究中，我们使用 MALDI-TOF MS 来定义三个 ALG2-CDG 患者的总血清蛋白和转铁蛋白（Tf）N-聚糖表型，这些患者均为纯合状态携带 c.752G>T，p.Arg251Leu ALG2 错义变异，该变异通过外显子组测序确定。将其与对照样本进行比较，我们观察到 Tf 糖基化位点（典型的缺陷 N-聚糖组装） occupancy 不足以及寡甘露糖和杂合型 N-聚糖的出现。此外，我们还观察到总血清糖谱中存在轻微的寡甘露糖积累。研究患者的血清 N-聚糖异质性增加表明 ALG2-CDG 中聚糖加工的轻微紊乱。先前的研究报道，由于 dolichol 连接寡糖生物合成中甘露糖化步骤的缺陷，CDG-I 中异常血清 N-聚糖的浓度略有增加。这项初步工作旨在考虑高甘露糖化糖型（如寡甘露糖和杂合型 N-聚糖）的血清 N-聚糖积累作为 ALG2-CDG 患者的潜在诊断信号。
