Figure 7.

A model for 5′ SS selection in exon 11 of LMNA. (A) In the wild-type sequence, usage of the alternative 5′ SS in hindered by stable base pairing with the downstream sequence. Thus, it is not as accessible as the normal 5′ SS which forms an unstable structure. While the positional advantage favors the alternative 5′ SS, this advantage is outweighed by the sequence and structure which favor selection of the normal 5′ SS. (B) In the case of the disease-causing C1824U mutation, the sequence advantage for the normal 5′ SS is not as potent as in the wild-type sequence. However, the positional advantage of the alternative 5′ SS shifts the balance to favor its selection. (C) ASO treatment interfering with the inhibitory structural elements of the alternative splice site confers the structural advantage to the alternative 5′ SS. Combined with the positional advantage, the alternative 5′ SS is selected even though the sequence favors the normal 5′ SS. (D) Reducing reactivity of the normal 5′ SS, by making the region more structurally stable, eliminates the structural advantage of the normal 5′ SS. The alternative 5′ SS is selected due to the positional advantage over the sequence advantage of the normal 5′ SS.