Many mutations in thin filament proteins have been found to be associated with inherited heart disease, notably, hypertrophic cardiomyopathy (HCM) and familial dilated cardiomyopathy (DCM). Importantly, such mutations commonly affect the PKA-dependent troponin modulatory system, either mimicking the Ca 2+ -sensitivity shifts caused by phosphorylation or interfering with them such that Ca 2+ -sensitivity becomes independent of phosphorylation level (uncoupling) . A well-studied example of this is the mutation in cardiac troponin C, cTnC G159D, that causes familial dilated cardiomyopathy and has also been shown to uncouple cTnI phosphorylation from modulation of Ca 2+ sensitivity (Figure ). Uncoupling results in blunting of the lusitropic response to β1 receptor stimulation and this has been proposed to be causative of the DCM phenotype .