Key result
LAMA4 and ILK mutations impair integrin binding in severe DCM.
Why the study?
Extracellular matrix proteins like laminins and endothelial cells influence cardiomyocyte performance, but the molecular mechanisms underlying this interaction are poorly understood.
Mutations in the laminin, integrin, and ILK system provide a new genetic basis for dilated cardiomyopathy in humans, affecting both cardiomyocytes and endothelial cells.
No immediate clinical implications for DCM; leaves open therapeutic targeting of laminin-integrin-ILK pathway pending validation.
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.
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Knöll et al. (2007) studied severe dilated cardiomyopathy. LAMA4 and ILK gene mutations vs. Wild-type genes was evaluated on Identification of mutations and integrin-binding capacity. Mutations in the LAMA4 and ILK genes were identified in patients with severe dilated cardiomyopathy, resulting in a loss of integrin-binding capacity compared with wild-type protein.
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