Interplay of primary sequence, position and secondary RNA structure determines alternative splicing of LMNA in a pre-mature aging syndrome.

ABSTRACT: Aberrant splicing in exon 11 of the LMNA gene causes the premature aging disorder Hutchinson-Gilford Progeria Syndrome. A de novo C1824T mutation activates an internal alternative 5' splice site, resulting in formation of the disease-causing progerin protein. The underlying mechanism for this 5' splice site selection is unknown. Here, we have applied a combination of targeted mutational analysis in a cell-based system and structural mapping by SHAPE-MaP to comprehensively probe the contributions of primary sequence, secondary RNA structure and linear splice site position in determining in vivo mechanisms of splice site choice in LMNA. While splice site choice is in part defined by sequence complementarity to U1 snRNA, we identify RNA secondary structural elements near the alternative 5' sp

SUBMITTER: Shilo A 

PROVIDER: S-EPMC6582319 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature