Characterization and Investigation of zebrafish models of Filamin related myofibrillar myopathy

Ruparelia, A.A., Zhao, M., Currie, P.D., and Bryson-Richardson, R.J.
Human molecular genetics   21(18): 4073-4083 (Journal)
Registered Authors
Bryson-Richardson, Robert, Currie, Peter D., Ruparelia, Avnika, Zhao, Mo
MeSH Terms
  • Animals
  • Animals, Genetically Modified
  • Base Sequence
  • Body Patterning/genetics
  • Codon, Nonsense
  • DNA Mutational Analysis
  • Disease Models, Animal*
  • Embryo, Nonmammalian/metabolism
  • Embryo, Nonmammalian/pathology
  • Filamins
  • Gene Expression
  • Gene Expression Regulation, Developmental
  • Gene Knockdown Techniques
  • Genetic Linkage
  • Humans
  • Likelihood Functions
  • Microfilament Proteins/genetics*
  • Microfilament Proteins/metabolism
  • Microfilament Proteins/physiology
  • Muscle Contraction
  • Muscle Fibers, Slow-Twitch/metabolism
  • Muscle Fibers, Slow-Twitch/pathology
  • Muscular Dystrophies/embryology
  • Muscular Dystrophies/genetics*
  • Mutagenesis
  • Myosins/metabolism
  • Phenotype
  • Phylogeny
  • Protein Isoforms/genetics
  • Protein Isoforms/metabolism
  • Protein Isoforms/physiology
  • Zebrafish/embryology
  • Zebrafish/genetics*
  • Zebrafish Proteins/genetics*
  • Zebrafish Proteins/metabolism
  • Zebrafish Proteins/physiology
22706277 Full text @ Hum. Mol. Genet.

Myofibrillar myopathies are a group of muscle disorders characterized by the disintegration of skeletal muscle fibers and formation of sarcomeric protein aggregates. All the proteins known to be involved in myofibrillar myopathies localize to a region of the sarcomere known as the Z-disk, the site at which defects are first observed. Given the common cellular phenotype observed in this group of disorders it is thought that there is a common mechanism of pathology. Mutations in Filamin C, which has several proposed roles in the development and function of skeletal muscle, can result in Filamin related myofibrillar myopathy. The lack of a suitable animal model system has limited investigation into the mechanism of pathology in this disease and the role of Filamin C in muscle development. Here we characterize stretched out (sot), a zebrafish filamin Cb mutant, together with targeted knockdown of zebrafish filamin Ca, revealing fiber dissolution and formation of protein aggregates strikingly similar to those seen in Filamin related myofibrillar myopathies. Through knockdown of both zebrafish Filamin C homologues we demonstrate that Filamin C is not required for fiber specification and that fiber damage is a consequence of muscle activity. The remarkable similarities in the myopathology between our models and Filamin related myofibrillar myopathy makes them suitable for the study of these diseases and provides unique opportunities for the investigation of the function of Filamin C in muscle and development of therapies.

Genes / Markers
Show all Figures
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes