gms | German Medical Science

Mutations in filamin C are among the identified disease causing mutations in myofibrillar myopathies. Filamin C is mainly expressed in the skeletal and cardiac muscle where it interacts with actin and several z-disk proteins. In zebrafish two filamin C orthologues are described, filamin C, a and filamin C, b. RNA in situ hybridizations showed similar expression patterns of both orthologues. Antisense oligonucleotide mediated knockdown of filamin C, a and filamin C, b resulted in a similar phenotype also the filamin C, b knockdown had a higher penetrance and showed a more severe phenotype. After filamin C knockdown we could observe a myopathic phenotype in the zebrafish larvae. They develop large pericardial edema and a significantly reduced heart rate within 48 hours post fertilization (hpf). Fractional shortening measurement showed that ventricular contractility of 72 hpf filamin C deficient zebrafish is only 19 % of control individuals. At this timepoint the embryos have no blood circulation as a result of the reduced heart function. The embryos are also immobile in a touch response test. Histopathological and ultrastructural analyses of filamin C-deficient embryos revealed a reduction of myofibrils in the skeletal and heart muscle, giving a possible explanation for the immobility of the embryos. Furthermore electron microscopic images showed detachment of the filaments, what could point to a loss of myofibrillar stability at the z-disks. RNA in situ hybridization showed filamin C expression in the developing skeletal muscle, indicating an involvement of filamin C in early muscle development. Immunofluorescent staining revealed normal development of the motoneurons, supporting our hypothesis that the immobility of the embryos results from a defect in myofibrillogenesis and is not due to neuronal alterations. We found no protein aggregates in our analyzes of the filamin C deficient zebrafish, as they are described in myofibrillar myopathy patient samples. Currently we are further investigating the function of filamin C in myofibrillogenesis by analyzing the ultra structural localization of filamin C and its interaction partners. In summary we observed a severe myopathic phenotype after filamin C knockdown in zebrafish, indicating that this might be a good model to study filamin C associated myopathy.