Laminin-alpha4 and integrin-linked kinase mutations cause human cardiomyopathy via simultaneous defects in cardiomyocytes and endothelial cells.
Laminin-alpha4 and integrin-linked kinase mutations cause human cardiomyopathy via simultaneous defects in cardiomyocytes and endothelial cells.
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发表时间：
2007
期刊：
影响因子：
37.8
通讯作者：
R. Knöll;R. Postel;Jianming Wang;R. Krätzner;G. Hennecke;A. Vacaru;Padmanabhan Vakeel;C. Schubert;Kenton K Murthy;B. Rana;D. Kube;G. Knöll;K. Schäfer;Takeharu Hayashi;T. Holm;A. Kimura;N. Schork;M. Toliat;P. Nürnberg;H. Schultheiss;W. Schaper;J. Schaper;E. Bos;J. den Hertog;F. V. van Eeden;P. Peters;G. Hasenfuss;K. Chien;J. Bakkers
中科院分区：
文献类型：
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作者：
R. Knöll;R. Postel;Jianming Wang;R. Krätzner;G. Hennecke;A. Vacaru;Padmanabhan Vakeel;C. Schubert;Kenton K Murthy;B. Rana;D. Kube;G. Knöll;K. Schäfer;Takeharu Hayashi;T. Holm;A. Kimura;N. Schork;M. Toliat;P. Nürnberg;H. Schultheiss;W. Schaper;J. Schaper;E. Bos;J. den Hertog;F. V. van Eeden;P. Peters;G. Hasenfuss;K. Chien;J. Bakkers
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.
