Beimdiek Julia, Hennig René, Burock Robert, Puk Oliver, Biskup Saskia, Rapp Erdmann, Lesinski-Schiedat Anke, Buettner Falk F R, Das Anibh M
Institute of Clinical Biochemistry, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
glyXera GmbH, Brenneckestraße 20, 39120 Magdeburg, Germany.
Glycobiology. 2022 Apr 21;32(5):380-390. doi: 10.1093/glycob/cwac003.
Rare genetic mutations of the mannosyl-oligosaccharide glucosidase (MOGS) gene affecting the function of the mannosyl-oligosaccharide glucosidase (glucosidase I) are the cause of the congenital disorder of glycosylation IIb (CDG-IIb). Glucosidase I specifically removes the distal α1,2-linked glucose from the protein bound precursor N-glycan Glc3Man9GlcNAc2, which is the initial step of N-glycan maturation. Here, we comparatively analyzed N-glycosylation of the whole serum proteome, serum-derived immunoglobulin G (IgG), transferrin (TF), and α-1-antitrypsin (AAT) of a female patient who is compound heterozygous for 2 novel missense mutations in the MOGS gene, her heterozygous parents, and a sibling with wildtype genotype by multiplexed capillary gel electrophoresis coupled to laser induced fluorescence detection (xCGE-LIF) at unprecedented depth. Thereby, we detected the CDG-IIb-characteristic non-de-glucosylated N-glycans Glc3Man7-9GlcNAc2 as well as the free tetrasaccharide Glc3-Man in whole serum of the patient but not in the other family members. The N-glycan analysis of the serum proteome further revealed that relative intensities of IgG-specific complex type di-antennary N-glycans with core-fucosylation were considerably reduced in the patient's serum whereas TF- and AAT-characteristic sialylated di- and tri-antennary N-glycans were increased. This finding reflected the hypogammaglobulinemia diagnosed in the patient. We further detected aberrant oligo-mannose (Glc3Man7GlcNAc2) and hybrid type N-glycans on patient-derived IgGs and we attributed this defective glycosylation to be the reason for an increased IgG clearance. This mechanism can explain the hypogammaglobulinemia that is associated with CDG-IIb.
影响甘露糖基寡糖葡糖苷酶（葡糖苷酶I）功能的甘露糖基寡糖葡糖苷酶（MOGS）基因的罕见基因突变是糖基化先天性疾病IIb型（CDG-IIb）的病因。葡糖苷酶I特异性地从与蛋白质结合的前体N-聚糖Glc3Man9GlcNAc2中去除远端α1,2-连接的葡萄糖，这是N-聚糖成熟的第一步。在此，我们通过与激光诱导荧光检测联用的多重毛细管凝胶电泳（xCGE-LIF），以前所未有的深度，比较分析了一名女性患者及其杂合子父母和一名野生型基因型同胞的全血清蛋白质组、血清来源的免疫球蛋白G（IgG）、转铁蛋白（TF）和α-1-抗胰蛋白酶（AAT）的N-糖基化情况。该女性患者为MOGS基因中两个新型错义突变的复合杂合子。由此，我们在患者的全血清中检测到了CDG-IIb特征性的非去葡糖基化N-聚糖Glc3Man7-9GlcNAc2以及游离四糖Glc3-Man，而在其他家庭成员中未检测到。血清蛋白质组的N-聚糖分析进一步显示，患者血清中具有核心岩藻糖基化的IgG特异性复合型双天线N-聚糖的相对强度显著降低，而TF和AAT特征性的唾液酸化双天线和三天线N-聚糖则增加。这一发现反映了该患者被诊断出的低丙种球蛋白血症。我们还在患者来源的IgG上检测到了异常的寡甘露糖（Glc3Man7GlcNAc2）和杂合型N-聚糖，并将这种糖基化缺陷归因于IgG清除增加的原因。这一机制可以解释与CDG-IIb相关的低丙种球蛋白血症。
