title: In vivo characterization of human myofibrillar myopathy genes in zebrafish.
abstract: Myofibrillar myopathies (MFM) are progressive diseases of human heart and skeletal muscle with a severe impact on life quality and expectancy of affected patients. Although recently several disease genes for myofibrillar myopathies could be identified, today most genetic causes and particularly the associated mechanisms and signaling events that lead from the mutation to the disease phenotype are still mostly unknown. To assess whether the zebrafish is a suitable model system to validate MFM candidate genes using targeted antisense-mediated knock-down strategies, we here specifically inactivated known human MFM disease genes and evaluated the resulting muscular and cardiac phenotypes functionally and structurally. Consistently, targeted ablation of MFM genes in zebrafish led to compromised skeletal muscle function mostly due to myofibrillar degeneration as well as severe heart failure. Similar to what was shown in MFM patients, MFM gene-deficient zebrafish showed pronounced gene-specific phenotypic and structural differences. In summary, our results indicate that the zebrafish is a suitable model to functionally and structurally evaluate novel MFM disease genes in vivo.
authors: Department of Internal Medicine II, University of Ulm, 89081 Ulm, Germany.
authors: John B
authors: JB
authors: Bührdel
authors: Department of Internal Medicine II, University of Ulm, 89081 Ulm, Germany.
authors: Sofia
authors: S
authors: Hirth
authors: Department of Internal Medicine II, University of Ulm, 89081 Ulm, Germany.
authors: Mirjam
authors: M
authors: Kessler
authors: Department of Internal Medicine II, University of Ulm, 89081 Ulm, Germany.
authors: Sören
authors: S
authors: Westphal
authors: Department of Internal Medicine II, University of Ulm, 89081 Ulm, Germany.
authors: Monika
authors: M
authors: Forster
authors: Department of Internal Medicine II, University of Ulm, 89081 Ulm, Germany.
authors: Linda
authors: L
authors: Manta
authors: Department of Biochemistry and Cell Biology, Max F. Perutz Laboratories, University of Vienna, 1030 Vienna, Austria.
authors: Gerhard
authors: G
authors: Wiche
authors: Department of Neurology, Friedrich-Baur-Institut, Ludwig-Maximilians-University, Munich, Germany.
authors: Benedikt
authors: B
authors: Schoser
authors: Department of Neurology, Friedrich-Baur-Institut, Ludwig-Maximilians-University, Munich, Germany.
authors: Joachim
authors: J
authors: Schessl
authors: Institute of Neuropathology, University Hospital Erlangen, 91054 Erlangen, Germany.
authors: Rolf
authors: R
authors: Schröder
authors: Institute for Biochemistry I, University of Cologne, 50931 Köln, Germany.
authors: Christoph S
authors: CS
authors: Clemen
authors: Institute for Biochemistry I, University of Cologne, 50931 Köln, Germany.
authors: Ludwig
authors: L
authors: Eichinger
authors: Institute for Cell Biology, University of Bonn, 53121 Bonn, Germany.
authors: Dieter O
authors: DO
authors: Fürst
authors: Institute for Cell Biology, University of Bonn, 53121 Bonn, Germany.
authors: Peter F M
authors: PF
authors: van der Ven
authors: Department of Internal Medicine II, University of Ulm, 89081 Ulm, Germany. Electronic address: Wolfgang.Rottbauer@uniklinik-ulm.de.
authors: Wolfgang
authors: W
authors: Rottbauer
authors: Department of Internal Medicine II, University of Ulm, 89081 Ulm, Germany. Electronic address: Steffen.Just@uniklinik-ulm.de.
authors: Steffen
authors: S
authors: Just
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D020022:Genetic Predisposition to Disease; D006333:Heart Failure / Q000235:genetics / Q000473:pathology; D006801:Humans; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D020914:Myopathies, Structural, Congenital / Q000235:genetics / Q000473:pathology; D015027:Zebrafish / Q000235:genetics*
keywords: Cardiac muscle; Myofibrillar myopathy; Reverse genetics; Skeletal muscle; Zebrafish