Proteasome inhibitors increase missense mutated dysferlin in patients with muscular dystrophy

Azakir, B. A.; Erne, B.; Di Fulvio, S.; Stirnimann, Guido; Sinnreich, M. (2014). Proteasome inhibitors increase missense mutated dysferlin in patients with muscular dystrophy. Science translational medicine, 6(250), 250ra112-250ra112. American Association for the Advancement of Science 10.1126/scitranslmed.3009612

[img] Text
Proteasome inhibitors increase missense mutated.pdf - Published Version
Restricted to registered users only
Available under License Publisher holds Copyright.

Download (1MB) | Request a copy

No treatment is available for patients affected by the recessively inherited, progressive muscular dystrophies caused by a deficiency in the muscle membrane repair protein dysferlin. A marked reduction in dysferlin in patients harboring missense mutations in at least one of the two pathogenic DYSF alleles encoding dysferlin implies that dysferlin is degraded by the cell's quality control machinery. In vitro evidence suggests that missense mutated dysferlin might be functional if salvaged from degradation by the proteasome. We treated three patients with muscular dystrophy due to a homozygous Arg555Trp mutation in dysferlin with the proteasome inhibitor bortezomib and monitored dysferlin expression in monocytes and in skeletal muscle by repeated percutaneous muscle biopsy. Expression of missense mutated dysferlin in the skeletal muscle and monocytes of the three patients increased markedly, and dysferlin was correctly localized to the sarcolemma of muscle fibers on histological sections. Salvaged missense mutated dysferlin was functional in a membrane resealing assay in patient-derived muscle cells treated with three different proteasome inhibitors. We conclude that interference with the proteasomal system increases expression of missense mutated dysferlin, suggesting that this therapeutic strategy may benefit patients with dysferlinopathies and possibly other genetic diseases.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Hepatologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Hepatologie

?? DCD5A442C6AAE17DE0405C82790C4DE2 ??

UniBE Contributor:

Stirnimann, Guido

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1946-6234

Publisher:

American Association for the Advancement of Science

Language:

English

Submitter:

Lilian Karin Smith-Wirth

Date Deposited:

16 Apr 2015 14:27

Last Modified:

06 Nov 2015 09:47

Publisher DOI:

10.1126/scitranslmed.3009612

PubMed ID:

25143362

BORIS DOI:

10.7892/boris.66946

URI:

https://boris.unibe.ch/id/eprint/66946

Actions (login required)

Edit item Edit item
Provide Feedback