Pervasive mislocalization of pathogenic coding variants underlying human disorders.
Pervasive mislocalization of pathogenic coding variants underlying human disorders.
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人类疾病背后的致病编码变异普遍存在错误定位。
DOI：
10.1101/2023.09.05.556368
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发表时间：
2023
期刊：
影响因子：
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作者：
Lacoste,Jessica;Haghighi,Marzieh;Haider,Shahan;Lin,Zhen-Yuan;Segal,Dmitri;Reno,Chloe;Qian,WesleyWei;Xiong,Xueting;Shafqat-Abbasi,Hamdah;Ryder,PearlV;Senft,Rebecca;Cimini,BethA;Roth,FrederickP;Calderwood,Michael;Hill,David;
广泛的测序已经产生了数以千计的错义变异，被预测或确认为致病因素。这就产生了一个新的瓶颈：确定每个变异的功能影响--通常是一个艰苦的定制过程，一次承担一个或几个基因和变异。在这里，我们建立了一个高通量成像平台来分析编码变异对蛋白质定位的影响，评估了超过1,000个基因和表型的3,448个错义变体。我们发现定位错误是编码变异的常见后果，影响到所有致病错义变体的六分之一，所有细胞隔室，以及隐性和显性疾病。错误定位主要是由于对蛋白质稳定性和膜插入的影响，而不是运输信号或特定相互作用的中断。此外，错误定位模式有助于解释多效性和疾病严重性，并提供对不确定意义的变异的见解。我们的公开资源扩展了我们对人类疾病编码变异的理解。
Widespread sequencing has yielded thousands of missense variants predicted or confirmed as disease causing. This creates a new bottleneck: determining the functional impact of each variant—typically a painstaking, customized process undertaken one or a few genes and variants at a time. Here, we established a high-throughput imaging platform to assay the impact of coding variation on protein localization, evaluating 3,448 missense variants of over 1,000 genes and phenotypes. We discovered that mislocalization is a common consequence of coding variation, affecting about one-sixth of all pathogenic missense variants, all cellular compartments, and recessive and dominant disorders alike. Mislocalization is primarily driven by effects on protein stability and membrane insertion rather than disruptions of trafficking signals or specific interactions. Furthermore, mislocalization patterns help explain pleiotropy and disease severity and provide insights on variants of uncertain significance. Our publicly available resource extends our understanding of coding variation in human diseases.