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          Institute: MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut)     Collection: Publikationen des W. G. Kerckhoff-Instituts     Display Documents

ID: 354748.0, MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut) / Publikationen des W. G. Kerckhoff-Instituts
Laminin-alpha4 and integrin-linked kinase mutations cause human cardiomyopathy via simultaneous defects in cardiomyocytes and endothelial cells
Authors:Knoll, R.; Postel, R.; Wang, J.; Kratzner, R.; Hennecke, G.; Vacaru, A. M.; Vakeel, P.; Schubert, C.; Murthy, K.; Rana, B. K.; Kube, D.; Knoll, G.; Schafer, K.; Hayashi, T.; Holm, T.; Kimura, A.; Schork, N.; Toliat, M. R.; Nurnberg, P.; Schultheiss, H. P.; Schaper, W.; Schaper, J.; Bos, E.; Den Hertog, J.; van Eeden, F. J.; Peters, P. J.; Hasenfuss, G.; Chien, K. R.; Bakkers, J.
Date of Publication (YYYY-MM-DD):2007-07-31
Journal Abbrev.:Circulation
Issue / Number:5
Start Page:515
End Page:525
Audience:Not Specified
Abstract / Description:BACKGROUND: Extracellular matrix proteins, such as laminins, and endothelial cells are known to influence cardiomyocyte performance; however, the underlying molecular mechanisms remain poorly understood. METHODS AND RESULTS: We used a forward genetic screen in zebrafish to identify novel genes required for myocardial function and were able to identify the lost-contact (loc) mutant, which encodes a nonsense mutation in the integrin-linked kinase (ilk) gene. This loc/ilk mutant is associated with a severe defect in cardiomyocytes and endothelial cells that leads to severe myocardial dysfunction. Additional experiments revealed the epistatic regulation between laminin-alpha4 (Lama4), integrin, and Ilk, which led us to screen for mutations in the human ILK and LAMA4 genes in patients with severe dilated cardiomyopathy. We identified 2 novel amino acid residue-altering mutations (2828C>T [Pro943Leu] and 3217C>T [Arg1073X]) in the integrin-interacting domain of the LAMA4 gene and 1 mutation (785C>T [Ala262Val]) in the ILK gene. Biacore quantitative protein/protein interaction data, which have been used to determine the equilibrium dissociation constants, point to the loss of integrin-binding capacity in case of the Pro943Leu (Kd=5+/-3 micromol/L) and Arg1073X LAMA4 (Kd=1+/-0.2 micromol/L) mutants compared with the wild-type LAMA4 protein (Kd=440+/-20 nmol/L). Additional functional data point to the loss of endothelial cells in affected patients as a direct consequence of the mutant genes, which ultimately leads to heart failure. CONCLUSIONS: This is the first report on mutations in the laminin, integrin, and ILK system in human cardiomyopathy, which has consequences for endothelial cells as well as for cardiomyocytes, thus providing a new genetic basis for dilated cardiomyopathy in humans.
Free Keywords:Adult; Amino Acid Substitution; Animals; COS Cells; Cardiomyopathy, Dilated/*genetics/metabolism/pathology; Cell Adhesion; Cercopithecus aethiops; Chromosome Mapping; Codon, Nonsense; DNA Mutational Analysis; Embryo, Nonmammalian/pathology; Endothelial Cells/*pathology; Epigenesis, Genetic; Extracellular Matrix/metabolism/pathology; Female; Heart/embryology; Heart Failure/etiology/pathology; Humans; Integrins/metabolism; Laminin/*genetics/physiology; Male; Middle Aged; Models, Molecular; *Mutation, Missense; Myocardium/pathology; Myocytes, Cardiac/*pathology; Oligonucleotides, Antisense/toxicity; Pedigree; *Point Mutation; Protein Binding; Protein Conformation; Protein Interaction Mapping; Protein Structure, Tertiary; Protein-Serine-Threonine Kinases/*genetics/physiology; Transfection; Zebrafish/embryology/genetics; Zebrafish Proteins/genetics/physiology
External Publication Status:published
Document Type:Article
Communicated by:N. N.
Affiliations:MPI für physiologische und klinische Forschung
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