Molecular Basis and Therapeutic Strategies to Rescue Factor IX Variants That Affect Splicing and Protein Function

Mutations that result in amino acid changes can affect both pre-mrna splicing and protein function. understanding the combined effect is essential for correct diagnosis and for establishing the most appropriate therapeutic strategy at the molecular level. we have identified a series of disease-causing splicing mutations in coagulation factor ix (fix) exon 5 that are completely recovered by a modified u1snrnp particle,through an srsf2-dependent enhancement mechanism. we discovered that synonymous mutations and missense substitutions associated to a partial fix secretion defect represent targets for this therapy as the resulting spliced-corrected proteins maintains normal fix coagulant specific activity. thus,splicing and protein alterations contribute to define at the molecular level the disease-causing effect of a number of exonic mutations in coagulation fix exon 5. in addition,our results have a significant impact in the development of splicing-switching therapies in particular for mutations that affect both splicing and protein function where increasing the amount of a correctly spliced protein can circumvent the basic functional defects. © 2016 tajnik et al.