Modeling a congenital disorder of glycosylation type I in C. elegans: a genome-wide RNAi screen for N-glycosylation-dependent loci.
Modeling a congenital disorder of glycosylation type I in C. elegans: a genome-wide RNAi screen for N-glycosylation-dependent loci.
复制标题
建立秀丽隐杆线虫 I 型先天性糖基化疾病模型：针对 N-糖基化依赖性位点的全基因组 RNAi 筛选。
DOI：
10.1093/glycob/cwp136
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发表时间：
2009
期刊：
影响因子：
4.3
通讯作者：
Warren,CharlesE
中科院分区：
文献类型：
--
作者：
Struwe,WestonB;Hughes,BethanyL;Osborn,DavidW;Boudreau,EricaD;Shaw,KristinMD;Warren,CharlesE
脂联寡糖供体合成缺陷引起的低效糖基化可导致多系统综合征，称为先天性I型糖基化紊乱(CDG-I)。严重的功能丧失突变是胚胎致命的，部分功能丧失的患者偶尔会出生，但病情很严重，几乎每个组织都有缺陷。CDG-I的临床表现差异很大，从非常轻微到严重不等，其不同临床特征的潜在原因尚不清楚。我们推测，个体遗传背景中伴随的缺陷会增加CDG-I临床表型的严重性。由于在CDG-I疾病中有如此多的蛋白质结构和功能受损，依赖于N连接的糖基化而导致致命性或特定症状的基因产物很难解决。基因沉默的力量，这是FC的特征。Eleganshas使我们能够系统地将在CDG-I患者中观察到的复杂糖基化表型分解成特定的糖依赖基因产物。为了实现这一点，我们用亚表型剂量的衣霉素抑制糖基化，通过RNA干扰减少单基因，然后寻找组合导致合成表型或显著增强表型的基因座。此屏幕已识别出Genees Inc.。需要N-连接的糖链才能正常发挥作用的雅培病毒，以及可能提高人类CDG-I疾病临床严重性的候选基因同源物。
Inefficient glycosylation caused by defective synthesis of lipid-linked oligosaccharide donor results in multi-systemic syndromes known as congenital disorders of glycosylation type I (CDG-I). Strong loss of function mutations are embryonic lethal, patients with partial losses of function are occasionally born but are very ill, presenting with defects in virtually every tissue. CDG-I clinical expression varies considerably and ranges from very mild to severe, and the underlying cause of the variable clinical features is not yet understood. We postulate that accompanying defects in an individual's genetic background enhance the severity of CDG-I clinical phenotypes. Since so many protein structures and functions are compromised in CDG-I illnesses, the gene products that are dependent onN-linked glycosylation which cause lethality or particular symptoms are difficult to resolve. The power of genetic silencing that is a characteristic ofC. eleganshas allowed us to systematically dissect the complex glycosylation phenotype observed in CDG-I patients into specific glycan-dependent gene products. To accomplish this, we inhibited glycosylation with a sub-phenotypic dose of tunicamycin, reduced single genes by RNA interference, and then sought loci where the combination caused a synthetic or dramatically enhanced phenotype. This screen has identified genes inC. elegansthat requireN-linked glycans to function properly as well as candidate gene homologues that may enhance the clinical severity of CDG-I disorders in humans.