De novo phosphoinositide synthesis in zebrafish is required for triad formation but not essential for myogenesis

Smith, Lindsay; Fabian, Lacramioara; Al‐Maawali, Almundher; Noche, Ramil R.; Dowling, James J.

doi:10.1371/journal.pone.0231364

Cited by 3 publications

(1 citation statement)

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“…Swimming behaviour of 7dpf zebrafish larvae was monitored using the Zebrabox platform (Viewpoint Behaviour Technology, Lyon, France), as previously described [ 56 , 57 ]. Briefly, zebrafish larvae were placed into 96-well plates in 150 µl system water and treated with the optovin analogue 6b8 (ChemBridge, #5707191) at 10 µM final concentration to promote motor behaviour.…”

Section: Methodsmentioning

confidence: 99%

Comprehensive phenotypic characterization of an allelic series of zebrafish models of NEB-related nemaline myopathy

Fabian,

Karimi,

Farman

et al. 2024

Human Molecular Genetics

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Nemaline myopathy (NM) is a rare congenital neuromuscular disorder characterized by muscle weakness and hypotonia, slow gross motor development, and decreased respiratory function. Mutations in at least twelve genes, all of each encode proteins that are either components of the muscle thin filament or regulate its length and stability, have been associated with NM. Mutations in Nebulin (NEB), a giant filamentous protein localized in the sarcomere, account for more than 50% of NM cases. At present, there remains a lack of understanding of whether NEB genotype influences nebulin function and NM-patient phenotypes. In addition, there is a lack of therapeutically tractable models that can enable drug discovery and address the current unmet treatment needs of patients. To begin to address these gaps, here we have characterized five new zebrafish models of NEB-related NM. These mutants recapitulate most aspects of NEB-based NM, showing drastically reduced survival, defective muscle structure, reduced contraction force, shorter thin filaments, presence of electron-dense structures in myofibers, and thickening of the Z-disks. This study represents the first extensive investigation of an allelic series of nebulin mutants, and thus provides an initial examination in pre-clinical models of potential genotype-phenotype correlations in human NEB patients. It also represents the first utilization of a set of comprehensive outcome measures in zebrafish, including correlation between molecular analyses, structural and biophysical investigations, and phenotypic outcomes. Therefore, it provides a rich source of data for future studies exploring the NM pathomechanisms, and an ideal springboard for therapy identification and development for NEB-related NM.

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Section: Methodsmentioning

confidence: 99%