Evaluation of both exonic and intronic variants for effects on RNA splicing allows for accurate assessment of the effectiveness of precision therapies

by Anya T. Joynt, Taylor A. Evans, Matthew J. Pellicore, Emily F. Davis-Marcisak, Melis A. Aksit, Alice C. Eastman, Shivani U. Patel, Kathleen C. Paul, Derek L. Osorio, Alyssa D. Bowling, Calvin U. Cotton, Karen S. Raraigh, Natalie E. West, Christian A. Merlo, Garry R. Cutting, Neeraj Sharma Elucidating the functional consequence of molecular defects underlying genetic diseases enables appropriate design of therapeutic options. Treatment of cystic fibrosis (CF) is an exemplar of this paradigm as the development of CFTR modulator therapies has allowed for targeted and effective treatme nt of individuals harboring specific genetic variants. However, the mechanism of these drugs limits effectiveness to particular classes of variants that allow production of CFTR protein. Thus, assessment of the molecular mechanism of individual variants is imperative for proper assignment of these p recision therapies. This is particularly important when considering variants that affect pre-mRNA splicing, thus limiting success of the existing protein-targeted therapies. Variants affecting splicing can occur throughout exons and introns and the complexity of the process of splicing lends itself to a variety of outcomes, both at the RNA and protein levels, further complicating assessment of disease liability and modulator response. To investigate the scope of this challenge, we evaluated splicing and downstream effects of 52 naturally occurringCFTR variants (exonic = 15, intronic = 37). Expressio...
Source: PLoS Genetics - Category: Genetics & Stem Cells Authors: Source Type: research