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57th Annual Meeting of the German Society for Neuropathology and Neuroanatomy (DGNN)

German Society for Neuropathology and Neuroanatomy

12. - 15.09.2012, Erlangen

57th Annual Meeting of the German Society for Neuropathology and Neuroanatomy (DGNN)

Loss of VCP leads to a myopathic phenotype

Meeting Abstract

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  • presenting/speaker Linda Gärtner - University Hospital Ulm, Internal Medicine 2, Ulm, Germany
  • Wolfgang Rottbauer - University Hospital Ulm, Internal Medicine 2, Ulm, Germany
  • Steffen Just - University Hospital Ulm, Internal Medicine 2, Ulm, Germany

Deutsche Gesellschaft für Neuropathologie und Neuroanatomie. 57th Annual Meeting of the German Society for Neuropathology and Neuroanatomy (DGNN). Erlangen, 12.-15.09.2012. Düsseldorf: German Medical Science GMS Publishing House; 2012. Doc12dgnnOP02

doi: 10.3205/12dgnn002, urn:nbn:de:0183-12dgnn0024

Published: September 11, 2012

© 2012 Gärtner et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( You are free: to Share – to copy, distribute and transmit the work, provided the original author and source are credited.



Myofibrillar myopathies (MFM) are progressive diseases of the heart and skeletal muscle that often lead to physical disability and premature death. Although several disease genes for MFM are known, the molecular pathomechanisms that translate the gene mutation into the myopathic phenotype are completely unknown. The zebrafish is an excellent model organism to examine the molecular pathology of human diseases.

One of the genes known to cause MFM in human is the valosin containing protein (VCP). To elucidate the role of VCPin vivo,we inactivated the zebrafish orthologue of the human VCP by injection of Morpholino-modified antisense oligonucleotides (MO-VCP) into one-cell stage zebrafish embryos. Control Morpholino-injected zebrafish embryos are unaffected at 72 hours post fertilization (hpf), whereas 80% of MO-VCP-injected zebrafish embryos developed severe contractile dysfunction, tail curvature and impaired motility. VCP morphants develop pericardial edema and show a progressive reduction of systolic heart function, which was determined by fractional shortening (fs) measurements of the ventricle between 48 and 96 hpf. VCP morphants also display severe skeletal muscle dysfunction. Tactile stimulation of zebrafish embryos usually results in a powerful and directed flight response. Touch stimulation of VCP morphants only results in a short shiver response. To verify whether this phenotype is caused by a muscular or neuronal problem, we analyzed the muscle structure and ultrastructure as well as the morphogenesis of neurons of the morphants. Interestingly, immunostainings against acetylated tubulin, a marker for growing axons, revealed only a slight reduction of the signal intensity of the caudal neuronal tube in VCP morphants. Therefore the impaired movement seems to be caused by a muscular defect. Although early somitogenesis markers such as MyoD or MyoG were normally expressed, the histopathological and ultrastructural examination reveals dramatic reduction of sarcomers in MO-VCP injected zebrafish. By transient and transgenic overexpression of zebrafish and human VCP mutations in the zebrafish model, we will now investigate thein vivorole of disease causing VCP mutations and characterize the molecular mechanisms that translate these mutations into the observed myopathic phenotypes.