Glycosyltransferase genes that cause monogenic congenital disorders of glycosylation are distinct from glycosyltransferase genes associated with complex diseases
Glycosyltransferase genes that cause monogenic congenital disorders of glycosylation are distinct from glycosyltransferase genes associated with complex diseases
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DOI：
10.1093/glycob/cwy015
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发表时间：
2018-05-01
期刊：
影响因子：
4.3
通讯作者：
Schjoldager, Katrine T.
中科院分区：
文献类型：
--
作者：
Joshi, Hiren J.;Hansen, Lars;Schjoldager, Katrine T.
人类细胞中蛋白质、脂质和蛋白聚糖的糖基化涉及至少 167 种已鉴定的糖基转移酶 (GTf)，这些酶协调不同类型糖复合物和聚糖结构的生物合成。 GTf 基因组这部分基因组的突变会导致超过 58 种罕见的单基因先天性糖基化疾病 (CDG)。根据全基因组关联研究 (GWAS)，它们在统计上还与大量复杂的表型、疾病或复杂疾病的易感性相关。 CDG 极为罕见，并且通常会带来严重的医疗后果。相比之下，GWAS 可能会识别出更常见的遗传变异，并且通常涉及不太严重和独特的性状。我们最近证实 GTf 基因的结构缺陷极为罕见，这似乎与大量 GWAS 指向 GTf 基因的情况不一致。为了解决这个问题，我们调查了 GTf 基因组以查找报告的 CDG 和 GWAS 候选者；我们发现两组基因之间几乎没有重叠。此外，CDG 或 GWAS 涉及的 GTf 基因似乎在以下方面构成不同的类别：（i）在糖基化途径中的预测作用； (ii) 紧密同源基因产生部分冗余的可能性； (iii) 通过 RNAseq 数据评估转录调控。我们的分析表明，更复杂的性状是由 GTf 的失调而不是结构缺陷引起的，这表明一些糖基化反应可能会受到严格的调节，以微调重要的生物功能。
Glycosylation of proteins, lipids and proteoglycans in human cells involves at least 167 identified glycosyltransferases (GTfs), and these orchestrate the biosynthesis of diverse types of glycoconjugates and glycan structures. Mutations in this part of the genome the GTf-genome cause more than 58 rare, monogenic congenital disorders of glycosylation (CDGs). They are also statistically associated with a large number of complex phenotypes, diseases or predispositions to complex diseases based on Genome-Wide Association Studies (GWAS). CDGs are extremely rare and often with severe medical consequences. In contrast, GWAS are likely to identify more common genetic variations and generally involve less severe and distinct traits. We recently confirmed that structural defects in GTf genes are extremely rare, which seemed at odds with the large number of GWAS pointing to GTf-genes. To resolve this issue, we surveyed the GTf-genome for reported CDGs and GWAS candidates; we found little overlap between the two groups of genes. Moreover, GTf-genes implicated by CDG or GWAS appear to constitute different classes with respect to their: (i) predicted roles in glycosylation pathways; (ii) potential for partial redundancy by closely homologous genes; and (iii) transcriptional regulation as evaluated by RNAseq data. Our analysis suggest that more complex traits are caused by dysregulation rather than structural deficiency of GTfs, which suggests that some glycosylation reactions may be predicted to be under tight regulation for fine-tuning of important biological functions.