Human Mutated MYOT and CRYAB Genes Cause a Myopathic Phenotype in Zebrafish

Author:

Cannone Elena1ORCID,Guglielmi Valeria2,Marchetto Giulia2ORCID,Tobia Chiara1ORCID,Gnutti Barbara1ORCID,Cisterna Barbara3ORCID,Tonin Paola2,Barbon Alessandro1ORCID,Vattemi Gaetano2ORCID,Schiavone Marco1ORCID

Affiliation:

1. Department of Molecular and Translational Medicine, Zebrafish Facility, University of Brescia, 25123 Brescia, Italy

2. Department of Neurosciences, Biomedicine and Movement Sciences, Section of Clinical Neurology, University of Verona, 37134 Verona, Italy

3. Department of Neurosciences, Biomedicine and Movement Sciences, Section of Anatomy and Histology, University of Verona, 37134 Verona, Italy

Abstract

Myofibrillar myopathies (MFMs) are a group of hereditary neuromuscular disorders sharing common histological features, such as myofibrillar derangement, Z-disk disintegration, and the accumulation of degradation products into protein aggregates. They are caused by mutations in several genes that encode either structural proteins or molecular chaperones. Nevertheless, the mechanisms by which mutated genes result in protein aggregation are still unknown. To unveil the role of myotilin and αB-crystallin in the pathogenesis of MFM, we injected zebrafish fertilized eggs at the one-cell stage with expression plasmids harboring cDNA sequences of human wildtype or mutated MYOT (p.Ser95Ile) and human wildtype or mutated CRYAB (p.Gly154Ser). We evaluated the effects on fish survival, motor behavior, muscle structure and development. We found that transgenic zebrafish showed morphological defects that were more severe in those overexpressing mutant genes. which developed a myopathic phenotype consistent with that of human myofibrillar myopathy, including the formation of protein aggregates. Results indicate that pathogenic mutations in myotilin and αB-crystallin genes associated with MFM cause a structural and functional impairment of the skeletal muscle in zebrafish, thereby making this non-mammalian organism a powerful model to dissect disease pathogenesis and find possible druggable targets.

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

Reference63 articles.

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