Balancing N-linked glycosylation to avoid disease
Balancing N-linked glycosylation to avoid disease
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DOI：
10.1016/s0300-9084(01)01292-5
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发表时间：
2001-08-01
期刊：
影响因子：
3.9
通讯作者：
Westphal, V
中科院分区：
文献类型：
--
作者：
Freeze, HH;Westphal, V
在酵母和哺乳动物中，N-糖基化的完全丧失是致命的。一些限速生物合成步骤的实质性缺陷会导致人类先天性糖基化障碍（CDG）。患者有一系列的临床问题，包括不同程度的精神发育迟滞，肝功能障碍和肠道疾病。磷酸甘露糖变位酶（由PMM 2编码）中超过60个突变降低活性并引起CDG-Ia。PMM 2中的严重突变R141 H在纯合子时是致命的，但在大约1/70的北方欧洲人中是杂合子。另一种疾病CDG-Ic是由ALG 6突变引起的，ALG 6是一种用于脂质连接前体合成的α 1，3葡萄糖基转移酶，但该基因中也发生了一些高频率的功能损害突变。维持看似有害的突变意味着选择优势或正杂种优势。对此的一个可能的解释是，感染性病毒如乙型肝炎病毒和丙型肝炎病毒或其他严重依赖宿主N-糖基化的病毒的产生，当它们的外壳蛋白中只有一小部分被糖基化时，基本上被抑制。相反，这种减少的糖基化不影响宿主。限速糖基化步骤中的流行功能突变可以提供对病毒感染的一些抗性，但这种保险的成本是CDG。平衡的糖基化水平试图适应这些竞争议程。通过评估多基因疾病中一系列N-糖基化损害等位基因的发生，有可能确定糖基化受损是否是其病理基础的风险因素或主要决定因素。(C)2001法国生物化学与生物分子学会/科学与医学版Elsevier SAS。All rights reserved.
Complete loss of N-glycosylation is lethal in both yeast and mammals. Substantial deficiencies in some rate-limiting biosynthetic steps cause human congenital disorders of glycosylation (CDG). Patients have a range of clinical problems including variable degrees of mental retardation, liver dysfunction, and intestinal disorders. Over 60 mutations in phosphomannomutase (encoded by PMM2) diminish activity and cause CDG-Ia. The severe mutation R141H in PMM2 is lethal when homozygous, but heterozygous in about 1/70 Northern Europeans. Another disorder, CDG-Ic, is caused by mutations in ALG6, an alpha1,3glucosyl transferase used for lipid-linked precursor synthesis, yet some function-compromising mutations occur at a high frequency in this gene also. Maintenance of seemingly deleterious mutations implies a selective advantage or positive heterosis. One possible explanation for this is that production of infective viruses such as hepatitis virus B and C, or others that rely heavily on host N-glycosylation, is substantially inhibited when only a tiny fraction of their coat proteins is misglycosylated. In contrast, this reduced glycosylation does not affect the host. Prevalent functional mutations in rate-limiting glycosylation steps could provide some resistance to viral infections, but the cost of this insurance is CDG. A balanced glycosylation level attempts to accommodate these competing agendas. By assessing the occurrence of a series of N-glycosylation-compromising alleles in multi-genic diseases, it may be possible to determine whether impaired glycosylation is a risk factor or a major determinant underlying their pathology. (C) 2001 Societe francaise de biochimie et biologic moleculaire/Editions scientifiques et medicales Elsevier SAS. All rights reserved.