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Conditional expression of mutant M-line titins results in cardiomyopathy with altered sarcomere structure

Item Type:Article
Title:Conditional expression of mutant M-line titins results in cardiomyopathy with altered sarcomere structure
Creators Name:Gotthardt, M. and Hammer, R.E. and Huebner, N. and Monti, J. and Witt, C.C. and McNabb, M. and Richardson, J.A. and Granzier, H. and Labeit, S. and Herz, J.
Abstract:Titin is a giant protein responsible for muscle elasticity and provides a scaffold for several sarcomeric proteins, including the novel titin-binding protein MURF-1, which binds near the titin M-line region. Another unique feature of titin is the presence of a serine/threonine kinase-like domain at the edge of the M-line region of the sarcomere, for which no physiological catalytic function has yet been shown. To investigate the role(s) of the titin M-line segment, we have conditionally deleted the exons MEx1 and MEx2 (encoding the kinase domain plus flanking sequences) at different stages of embryonic development. Our data demonstrate an important role for MEx1 and MEx2 in early cardiac development (embryonic lethality) as well as postnatally when disruption of M-line titin leads to muscle weakness and death at ∼5 weeks of age. Myopathic changes include pale M-lines devoid of MURF-1, and gradual sarcomeric disassembly. The animal model presented here indicates a critical role for the M-line region of titin in maintaining the structural integrity of the sarcomere.
Keywords:Actins, Bacterial Artificial Chromosomes, Binding Sites, Cardiomyopathies, Elasticity, Gene Expression Regulation, Genetic Recombination, Knockout Mice, Major Histocompatibility Complex, Molecular Cloning, Muscle Proteins, Myosin Heavy Chains, Organ Specificity, Promoter Regions, Protein Kinases, Sarcomeres, Skeletal Muscle, Stem Cells, Animals, Mice
Source:Journal of Biological Chemistry
ISSN:0021-9258
Publisher:American Society for Biochemistry and Molecular Biology (U.S.A.)
Volume:278
Number:8
Page Range:6059-6065
Date:21 February 2003
Official Publication:https://doi.org/10.1074/jbc.M211723200
PubMed:View item in PubMed

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