Allele-selective knockdown of mutant DNAJB6 improves molecular features in a primary mouse myotube model of LGMDD1

Allele-selective siRNA knockdown of mutant F90I DNAJB6 in primary Flag-LGMDD1 mouse myotubes shifts baseline and stress-linked proteostasis markers toward control values.

• Why it matters: Dominant DNAJB6 variants drive LGMDD1 via disrupted protein homeostasis, but complete DNAJB6 loss is embryonically lethal, limiting conventional knockouts.
• What they did: The study used a knock-in mouse with an N-terminal 3xFLAG tag on the wild-type Dnajb6 allele to measure endogenous wild-type and F90I DNAJB6, then screened siRNAs and applied a lead candidate with 264-fold selectivity for F90I DNAJB6 in primary myotubes.
• The result: In primary Flag-LGMDD1 myotubes, the selected siRNA selectively reduced F90I DNAJB6 and normalized abnormalities involving p62, HSP70, DNAJA4, and unfolded protein response signaling after proteostatic stress, supporting cellular proof of concept.

AI summary of the abstract · may contain errors · not medical advice · read the paper.