The present disclosure provides a cDNA,
protein sequence, and genomic structure of the human cardiac isoform of
myosin light chain
kinase (cMLCK), and describes mutations in the cMLCK
gene that are associated with
cardiac dysfunction. Methods are provided for identifying individuals who can harbor mutations in the cMLCK
gene, or carry alleles that can predisposed them to
cardiac dysfunction. Disclosed also is a significant role for cMLCK in modulating cardiac
contractility. The cMLCK
protein is shown herein to reduce the amplitude of stretch activation and increase the tension production, a property of
muscle which has heretofore had an unknown role in cardiac contraction. Moreover, the cMLCK
protein is shown to be regionally distributed in the heart, thereby having
differential effects on
contractility and stretch activation. Methods herein are provided to
exploit this effect of cMLCK, to treat individuals who have or are prone to
cardiac dysfunction. In addition, methods are provided to identify agents that modulate cMLCK activity, thereby having potential therapeutic importance in the treatment of cardiac dysfunction.