A humanized knock-in <i>Col6a1</i> mouse recapitulates a deep-intronic splice-activating variant.

ABSTRACT: Antisense therapeutics such as splice-modulating antisense oligonucleotides (ASOs) are promising tools to treat diseases caused by splice-altering intronic variants. However, their testing in animal models is hampered by the generally poor sequence conservation of the intervening sequences between human and other species. Here we aimed to model in the mouse a recurrent, deep-intronic, splice-activating, COL6A1 variant, associated with a severe form of Collagen VI-related muscular dystrophies (COL6-RDs), for the purpose of testing human-ready antisense therapeutics in vivo. The variant, c.930+189C>T, creates a donor splice site and inserts a 72-nt-long pseudoexon, which, when translated, acts in a dominant-negative manner, but which can be skipped with ASOs. We created a uniqu

SUBMITTER: Bolduc V 

PROVIDER: S-EPMC10996637 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature