PUBLICATION
Lysosomes and the pathogenesis of merosin-deficient congenital muscular dystrophy
- Authors
- Smith, S.J., Fabian, L., Sheikh, A., Noche, R., Cui, X., Moore, S.A., Dowling, J.J.
- ID
- ZDB-PUB-210928-11
- Date
- 2021
- Source
- Human molecular genetics 31(5): 733-747 (Journal)
- Registered Authors
- Keywords
- laminin alpha 2lysosomesmuscular dystrophyMDC1A
- MeSH Terms
-
- Zebrafish*/genetics
- Muscle, Skeletal/pathology
- Lysosomes/genetics
- Lysosomes/pathology
- Animals
- Transcription Factors
- Humans
- Laminin/genetics
- Muscular Dystrophies*/pathology
- PubMed
- 34568901 Full text @ Hum. Mol. Genet.
Citation
Smith, S.J., Fabian, L., Sheikh, A., Noche, R., Cui, X., Moore, S.A., Dowling, J.J. (2021) Lysosomes and the pathogenesis of merosin-deficient congenital muscular dystrophy. Human molecular genetics. 31(5):733-747.
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 TFEB, 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping