Figure 4

Altered splicing model for Friedreich ataxia (FRDA) [30]. On unaffected frataxin (FXN) alleles the repeat is too short to significantly impact splicing. However, once the repeat number exceeds 90, splicing factors that are normally involved in the proper splicing of the FXN gene become mislocalized such that normal splicing is prevented. This could be the result of binding of splicing factors to the repeat, preventing their normal assembly at the splice junctions. Alternatively, the unrestrained spread of these or other repeat-binding proteins, such as heterogeneous nuclear ribonucleoprotein (hnRNP) A1 [77], could block access of factors needed for proper splicing analogous to what has been proposed for HIV [78]. It may also be that the repeat sequesters serine/arginine (SR) proteins such as alternative splicing factor/splicing factor 2 (ASF/SF2). Since these proteins are is required for 5' splice site selection and cleavage [79], this could lead to a local deficiency at the splice site and thus the failure to efficiently remove intron 1.