Loss of Sidt2 in Mice Resembles Danon Disease and Results in Induction of a Type I Interferon Response with Increased Apoptosis

Barrios, MH; Nguyen, TA; Houweling, PJ; Frank, D; Garton, FC; Lidov, HG; Tsui, E; Garnham, AL; Ambardekar, AV; Smyth, GK; Mestroni, L; Cleveland, JC; Taylor, MRG; North, KN; Hunter, CP; Pang, KC

Author(s): Barrios, MH; Nguyen, TA; Houweling, PJ; Frank, D; Garton, FC; Lidov, HG; Tsui, E; Garnham, AL; Ambardekar, AV; Smyth, GK; Mestroni, L; Cleveland, JC; Taylor, MRG; North, KN; Hunter, CP; Pang, KC;
Details: Publication Year 2026-10-15,Volume 27,Issue #20,Page 9158
Journal Title: International Journal of Molecular Sciences
Abstract: SIDT2 is a lysosomal membrane protein that-together with LAMP2-has been implicated in a recently described process known as RNAutophagy. Mutations in LAMP2 have long been known to cause Danon disease, a rare lysosomal storage disorder that affects multiple organ systems including brain and skeletal muscle. Recently, we have shown that loss of SIDT2 function in both humans and mice causes brain dysfunction, and it has been previously observed that loss of SIDT2 in mice also leads to muscle damage and reduced muscle strength. Here, we show that changes in the skeletal muscle of Sidt2(-/-) mice are reminiscent of those seen in Danon disease as evidenced by accumulation of autophagic vacuoles with sarcolemmal features, selective atrophy of fast twitch fibers, and a shared alteration in gene expression. Moreover, we find that loss of SIDT2 not only leads to impaired autophagy in skeletal muscle as previously described but also stimulates a type I interferon response and increased apoptosis.
Publisher: MDPI
Keywords: Animals; *Apoptosis/genetics; *Interferon Type I/metabolism; Mice; Autophagy; *Glycogen Storage Disease Type IIb/metabolism/genetics/pathology; Muscle, Skeletal/metabolism/pathology; Mice, Knockout; Lysosomal Membrane Proteins/genetics; Disease Models, Animal; Lysosomal-Associated Membrane Protein 2; Nucleotide Transport Proteins; Danon disease; RNAutophagy; Sidt2; apoptosis; dsRNA; interferon response; linc-MD1; muscle
Research Division(s): Bioinformatics and Computational Biology
PubMed ID: 42941927
Publisher's Version: https://doi.org/10.3390/ijms27209158
Open Access at Publisher's Site: https://doi.org/10.3390/ijms27209158
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2026-11-03 08:45:06

Last Modified: 2026-11-03 08:45:22