Figure 6

Model of pathogenic mutation (αP3A23′G>A)-induced aberrant exon P3A inclusion that is antagonistically regulated by hnRNPs L and LL.

Early spliceosome complex formation on CHRNA1 pre-mRNA with alternative exon P3A are schematically shown. Large letters indicate functional binding of splicing factors, whereas small letters represent compromised binding of splicing factors. The sequence of point mutation in exon P3A (αP3A23′G>A) is underlined. (a) HnRNP L (L) binds to wild-type exon P3A and interacts with PTB through the proline-rich region (PRR), which stabilizes PTB binding to the upstream PPT (YYYY). The hnRNP L–PTB interaction prevents association of U2AF⁶⁵ (65) to PPT and U1 snRNP (U1) to the 5′ splice site. The formation of exon-defined E (EDE) complex is thus impaired, which leads to skipping of exon P3A. (b) The αP3A23′G>A-mutation switches binding of hnRNP L to hnRNP LL (LL). Lack of PRR in hnRNP LL fails to stabilize PTB binding to the upstream PPT, which allows binding of U1 snRNP (U1) and U2AF⁶⁵ (65) on pre-mRNA. The formation of the exon-defined E (EDE) complex facilitates inclusion of exon P3A.