A glycogene mutation map for discovery of diseases of glycosylation
A glycogene mutation map for discovery of diseases of glycosylation
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DOI：
10.1093/glycob/cwu104
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发表时间：
2015-02-01
期刊：
影响因子：
4.3
通讯作者：
Bennett, Eric P.
中科院分区：
文献类型：
--
作者：
Hansen, Lars;Lind-Thomsen, Allan;Bennett, Eric P.
蛋白质和脂质的糖基化涉及超过200种已知的糖基转移酶（GT），并且编码这些酶的许多基因中的有害缺陷引起统称为先天性糖基化病症（CDG）的病症。大多数已知的CDG是由影响全球糖基化的糖基因缺陷引起的。许多GT是同源同工酶家族的成员，单个同工酶的缺陷可能不会影响全局的糖基化。与此相一致的是，在这些较大的同工酶同源家族中，引起疾病的糖基似乎代表性不足。然而，全基因组关联研究已经确定了这些同工酶基因作为不同疾病的候选基因，但如果没有生物标志物，验证并不简单。大规模全外显子组测序（WES）提供了对例如群体中GT基因中的突变的访问，其可用于预测和/或分析功能性有害突变。在这里，我们构建了一个草案的功能突变地图的糖原，GlyMAP，从WES的一个相当同质的人口2000丹麦。我们对所有错义突变进行了编目，并使用预测算法、人工检查以及在碳水化合物活性酶家族GT 27的情况下对突变进行实验分析，以绘制有害突变。GlyMAP（http：glymap.glycomics.ku.dk）提供了糖基因组遗传稳定性的第一个全局视图，并且应该用作发现新的CDG的工具。
Glycosylation of proteins and lipids involves over 200 known glycosyltransferases (GTs), and deleterious defects in many of the genes encoding these enzymes cause disorders collectively classified as congenital disorders of glycosylation (CDGs). Most known CDGs are caused by defects in glycogenes that affect glycosylation globally. Many GTs are members of homologous isoenzyme families and deficiencies in individual isoenzymes may not affect glycosylation globally. In line with this, there appears to be an underrepresentation of disease-causing glycogenes among these larger isoenzyme homologous families. However, genome-wide association studies have identified such isoenzyme genes as candidates for different diseases, but validation is not straightforward without biomarkers. Large-scale whole-exome sequencing (WES) provides access to mutations in, for example, GT genes in populations, which can be used to predict and/or analyze functional deleterious mutations. Here, we constructed a draft of a functional mutational map of glycogenes, GlyMAP, from WES of a rather homogenous population of 2000 Danes. We cataloged all missense mutations and used prediction algorithms, manual inspection and in case of carbohydrate-active enzymes family GT27 experimental analysis of mutations to map deleterious mutations. GlyMAP (http://glymap.glycomics.ku.dk) provides a first global view of the genetic stability of the glycogenome and should serve as a tool for discovery of novel CDGs.