气候变化领域集成服务门户(CCPortal): Positive epistasis between disease-causing missense mutations and silent polymorphism with effect on mRNA translation velocity

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DOI	10.1073/pnas.2010612118
	Positive epistasis between disease-causing missense mutations and silent polymorphism with effect on mRNA translation velocity
	Rauscher R.; Bampi G.B.; Guevara-Ferrer M.; Santos L.A.; Joshi D.; Mark D.; Strug L.J.; Rommens J.M.; Ballmann M.; Sorscher E.J.; Oliver K.E.; Ignatova Z.
发表日期	2021
ISSN	00278424
卷号	118 期号:4
英文摘要	Epistasis refers to the dependence of a mutation on other mutation(s) and the genetic context in general. In the context of human disorders, epistasis complicates the spectrum of disease symptoms and has been proposed as a major contributor to variations in disease outcome. The nonadditive relationship between mutations and the lack of complete understanding of the underlying physiological effects limit our ability to predict phenotypic outcome. Here, we report positive epistasis between intragenic mutations in the cystic fibrosis transmembrane conductance regulator (CFTR)—the gene responsible for cystic fibrosis (CF) pathology. We identified a synonymous single-nucleotide polymorphism (sSNP) that is invariant for the CFTR amino acid sequence but inverts translation speed at the affected codon. This sSNP in cis exhibits positive epistatic effects on some CF disease–causing missense mutations. Individually, both mutations alter CFTR structure and function, yet when combined, they lead to enhanced protein expression and activity. The most robust effect was observed when the sSNP was present in combination with missense mutations that, along with the primary amino acid change, also alter the speed of translation at the affected codon. Functional studies revealed that synergistic alteration in ribosomal velocity is the underlying mechanism; alteration of translation speed likely increases the time window for establishing crucial domain–domain interactions that are otherwise perturbed by each individual mutation. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	CFTR; Cotranslational folding; Mutations; Synonymous SNP; Translation
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180892
作者单位	Biochemistry and Molecular Biology, Department of Chemistry, University of Hamburg, Hamburg, 20146, Germany; Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, United States; Children’s Healthcare of Atlanta, Atlanta, GA 30322, United States; Program in Genetics & Genome Biology, Hospital for Sick Children, Toronto, M5G 0A4, Canada; Department of Statistical Sciences, Computer Science and Division of Biostatistics, University of Toronto, Toronto, M5G 0A4, Canada; Pediatric Clinic, Universitätsmedizin, Rostock, 18057, Germany
推荐引用方式 GB/T 7714	Rauscher R.,Bampi G.B.,Guevara-Ferrer M.,et al. Positive epistasis between disease-causing missense mutations and silent polymorphism with effect on mRNA translation velocity[J],2021,118(4).
APA	Rauscher R..,Bampi G.B..,Guevara-Ferrer M..,Santos L.A..,Joshi D..,...&Ignatova Z..(2021).Positive epistasis between disease-causing missense mutations and silent polymorphism with effect on mRNA translation velocity.Proceedings of the National Academy of Sciences of the United States of America,118(4).
MLA	Rauscher R.,et al."Positive epistasis between disease-causing missense mutations and silent polymorphism with effect on mRNA translation velocity".Proceedings of the National Academy of Sciences of the United States of America 118.4(2021).