Lysosomes and the pathogenesis of merosin-deficient congenital muscular dystrophy

Sarah J Smith; Lacramioara Fabian; Adeel Sheikh; Ramil Noche; Xiucheng Cui; Steven A Moore; James J Dowling

doi:10.1093/hmg/ddab278

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Lysosomes and the pathogenesis of merosin-deficient congenital muscular dystrophy

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Lysosomes and the pathogenesis of merosin-deficient congenital muscular dystrophy

Sarah J Smith, Lacramioara Fabian, Adeel Sheikh, Ramil Noche, Xiucheng Cui, Steven A Moore and James J Dowling

Human molecular genetics, Vol.31(5), pp.733-747

09/25/2021

DOI: 10.1093/hmg/ddab278

PMCID: PMC9989739

PMID: 34568901

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Abstract

Abstract Congenital muscular dystrophy type 1A (MDC1A), the most common congenital muscular dystrophy in Western countries, is caused by recessive mutations in LAMA2, the gene encoding laminin alpha 2. Currently, no cure or disease modifying therapy has been successfully developed for MDC1A. Examination of patient muscle biopsies revealed altered distribution of lysosomes. We hypothesized that this redistribution was a novel and potentially druggable aspect of disease pathogenesis. We explored this hypothesis using candyfloss (caf), a zebrafish model of MDC1A. We found that lysosome distribution in caf zebrafish was also abnormal. This altered localization was significantly associated with fiber detachment and could be prevented by blocking myofiber detachment. Overexpression of transcription factor EB, a transcription factor that promotes lysosomal biogenesis, led to increased lysosome content and decreased fiber detachment. We conclude that genetic manipulation of the lysosomal compartment is able to alter the caf zebrafish disease process, suggesting that lysosome function may be a target for disease modification.

Details

Title: Subtitle: Lysosomes and the pathogenesis of merosin-deficient congenital muscular dystrophy
Creators: Sarah J Smith - University of Calgary
Lacramioara Fabian - Hospital for Sick Children
Adeel Sheikh - Hospital for Sick Children
Ramil Noche - Hospital for Sick Children
Xiucheng Cui - Hospital for Sick Children
Steven A Moore - University of Iowa
James J Dowling - University of Toronto
Resource Type: Journal article
Publication Details: Human molecular genetics, Vol.31(5), pp.733-747
DOI: 10.1093/hmg/ddab278
PMID: 34568901
PMCID: PMC9989739
NLM abbreviation: Hum Mol Genet
ISSN: 0964-6906
eISSN: 1460-2083
Grant note: name: CureCMD; DOI: 10.13039/501100000038, name: Natural Sciences and Engineering Research Council; name: Mogford Campbell Family Chair at the Hospital for Sick Children; DOI: 10.13039/100000002, name: NIH
Language: English
Date published: 09/25/2021
Academic Unit: Pathology
Record Identifier: 9984201528402771

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