Journal Article

Characterization and investigation of zebrafish models of filamin-related myofibrillar myopathy

Avnika A. Ruparelia, Mo Zhao, Peter D. Currie and Robert J. Bryson-Richardson

in Human Molecular Genetics

Volume 21, issue 18, pages 4073-4083
Published in print September 2012 | ISSN: 0964-6906
Published online June 2012 | e-ISSN: 1460-2083 | DOI:
Characterization and investigation of zebrafish models of filamin-related myofibrillar myopathy

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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.

Journal Article.  6363 words.  Illustrated.

Subjects: Genetics and Genomics

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