AI Article Synopsis
- Cystic fibrosis is caused by mutations in the CFTR gene, with about 12% of these mutations affecting pre-mRNA splicing; some synonymous substitutions may be mistakenly labeled as neutral.
- Computational methods predicted how these synonymous substitutions impact CFTR splicing, and tests confirmed two significant mutations that disrupt splicing, potentially altering the protein's function.
- The study highlights that traditional mutation analysis often misses splicing defects, particularly from synonymous mutations, and suggests using bioinformatics and minigene assays to better identify harmful mutations.
Article Abstract
Background: Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Over 1800 CFTR mutations have been reported, and about 12% of mutations are believed to impair pre-mRNA splicing. Given that several synthetic, non-splice-junction synonymous substitutions have been reported to alter splicing in CFTR, we predicted that naturally occurring synonymous substitutions may be erroneously classified as functionally neutral.
Methods: Computational tools were used to predict the effect of synonymous substitutions on CFTR pre-mRNA splicing. The functional consequences of selected substitutions were evaluated using a minigene splicing assay.
Results: Two synonymous mutations were shown to have a dramatic effect on CFTR pre-mRNA splicing, and consequently could alter protein integrity and phenotypic outcome.
Conclusions: Traditional methods of mutation analysis overlook splicing defects that occur at internal positions in coding exons, especially synonymous substitutions. We show that bioinformatics tools and minigene splicing assays are a potent combination to prioritize and identify mutations that cause aberrant CFTR pre-mRNA splicing.
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Source |
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3440543 | PMC |
| http://dx.doi.org/10.1016/j.jcf.2012.04.009 | DOI Listing |
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