Figure 4.

Splice-site-interdependency-based exon skipping rescue model. (A) Principle of rescue of Exon X skipping due to a noncanonical splice-site (NCSS) variant (NV) at the 3′ splice site (upper panel) by strengthening the 5′ splice site with a “rescue variant” (R, lower panel). (B) In normal splicing of Exon X, upon binding of splice junction sequence motifs by splice factors, additional splice factors will bind and define the exon, which is followed by the lariat configuration and normal splicing. Absence of one or more splice-enhancing motifs in Exon X makes this exon vulnerable to exon skipping when a NV variant is present, because the number of splice factors binding to Exon X is only just enough for exon definition. (C) In the presence of a NV in the 3′ splice site, insufficient splice factors will bind and there is no exon definition. (D) By strengthening the 5′ splice site with the “R”, additional splice proteins can bind and the exon definition and normal splicing are restored.