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

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.

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Publication Details

Journal
International Journal of Molecular Sciences
Published
2026-10-15
DOI
https://doi.org/10.3390/ijms27209158
Primary Topic
Autophagy in Disease and Therapy
Type
article
Field-Weighted Citation Impact
0.00

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article

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

Kathryn N. North, Fleur C. Garton, Ken C. Pang, Peter J. Houweling et al.
International Journal of Molecular Sciences
Autophagy in Disease and Therapy
article

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

Kathryn N. North, Fleur C. Garton, Ken C. Pang, Peter J. Houweling, Alexandra L. Garnham, Hart G.W. Lidov, Gordon K. Smyth, Daniel O. Frank, Marilou H. Barrios, Craig P. Hunter, Amrut V. Ambardekar, Tan A. Nguyen, Matthew R.G. Taylor, Luisa Mestroni, Ellen Tsui, Joseph C. Cleveland
article en

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.

International Journal of Molecular SciencesVol. 27(20)
Boston Children's Hospital (US), Royal Children's Hospital (AU), Harvard University (US), The University of Queensland (AU), The University of Melbourne (AU), Walter and Eliza Hall Institute of Medical Research (AU), Murdoch Children's Research Institute (AU), Institute for Molecular Bioscience (AU), University of Colorado Anschutz Medical Campus (US)
National Health and Medical Research Council, Colorado Clinical and Translational Sciences Institute
Good health and well-being
Openalex Percentile: Top 12%
Autophagy in Disease and Therapy
DOIOpen Access PDFOpenAlex
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