Positive epistasis between disease-causing missense mutations and silent polymorphism with effect on mRNA translation velocity
Robert Rauscher, Giovana Bampi, Marta Guevara‐Ferrer, Leonardo Santos, Disha Joshi, David R. Mark, Lisa J. Strug, Johanna M. Rommens, Manfred Ballmann, Eric J. Sorscher, Kathryn E. Oliver, Zoya Ignatova
Abstract
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.