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The mutation Gly99lys (E99K) in the cardiac actin (ACTC) gene has been found to cause hypertrophic cardiomyopathy (HCM) in 75 hypertrophic obstructive cardiomyopathy (HOCM) or LVNC patients. Transgenic mice expressing 50% E99K mutant cardiac actin in their hearts were generated and studied. Over 30% male and 70% female E99K mice died between 28 and 45 days. Anaesthetised 7-month-old male transgenic mice and their non-transgenic littermates were studied using in-vivo cine magnetic resonance imaging. Abnormal cardiac morphology and significantly lower ejection fractions and reduced stroke volumes were observed in the transgenic mice. Peak left ventricular ejection rates were reduced. Left ventricle function of 9-month-old female non-transgenic and transgenic mice were studied with an in-vivo conductance catheter. The transgenic mice had significantly reduced ejection fraction, increased end-diastolic pressure and impaired relaxation. Left ventricular dilation has been observed in these mice. We studied mutant actin by an in-vitro motility assay. Thin filaments were reconstituted with purified mouse f-actin and human heart tropomyosin and troponin. The E99K thin filaments had higher Ca2+ sensitivity than non-transgenic thin filaments. E99K actin thin filaments did not respond to troponin dephosphorylation. The ACTC E99K mouse reproduces many features of HCM, as observed in patients. The basic effect of the ACTC E99K mutation is increased Ca2+ sensitivity together with a blunted response to troponin I phosphorylation. The increased myofibrilar Ca2+ sensitivity may be sufficient to provoke arrhythmia and account for the high mortality at early ages. Hypertrophy may be a chronic response to Ca2+ overloading or due to energy depletion.