The rationale is provided by the process of “ribosome readthrough” over nonsense mutations that, by reverting premature translation termination, would restore protein biosynthesis. Although at low rate, this process can occur spontaneously, and account for residual levels of protein that in coagulation factor disorders might have relevant pathophysiological implications. So far, we provided evidence for residual FVII and FIX levels (~1%) associated to a few nonsense changes.
In the present project, through studies in vivo and in vitro, we propose to investigation on a panel of F9 nonsense mutations to verify the hypothesis that part of nonsense mutations found in severe HB patients are associated to residual FIX levels. If confirmed, we expect to assess whether these traces of FIX are related to the clinical phenotype of patients and their immunological complications. Moreover, it could suggest potential “high responders” to drugs inducing readthrough. The knowledge of “leaky” nonsense mutations, less prone to trigger immune-response, could help diagnosis and treatment. Results from this study on a limited patients’ number could boost a more extensive study in HB patients, and extended to hemophilia A
