Hypertrophic cardiomyopathy caused by a novel alpha-tropomyosin mutation (V95A) is associated with mild cardiac phenotype, abnormal calcium binding to troponin, abnormal myosin cycling, and poor prognosis

Background-We report hypertrophic cardiomyopathy (HCM) in a Spanish-America n family caused by a novel alpha -tropomyosin (TPM1) mutation and examine t he pathogenesis of the clinical disease by characterizing functional defect s in the purified mutant protein. Methods and Results-HCM was linked to the TPM1 gene (logarithm of the odds [LOD] score 3.17). Sequencing and restriction digestion analysis demonstrat ed a TPM1 mutation V95A that cosegregated with HCM. The mutation has been a ssociated with 13 deaths in 26 affected members (11 sudden deaths and 2 rel ated to heart failure), with a cumulative survival rate of 73+/-10% at the age of 40 years. Left ventricular wall thickness (mean 16+/-6 mm) and disea se penetrance (53%) were similar to those for the beta -myosin mutations L9 08V and G256E previously associated with a benign prognosis. Left ventricul ar hypertrophy was milder than with the beta -myosin mutation R403Q, but th e prognosis was similarly poor. With the use of recombinant tropomyosins, w e identified several functional alterations at the protein level. The mutat ion caused a 40% to 50% increase in calcium affinity in regulated thin fila ment-myosin subfragment-1 (S1) MgATPase assays, a 20% decrease in MgATPase rates in the presence of saturating calcium, a 5% decrease in unloaded shor tening velocity in in vitro motility assays, and no change in cooperative m yosin S1 binding to regulated thin filaments. Conclusions-In contrast to other reported TPM1 mutations, V95A-associated H CM exhibits unusual features of mild phenotype but poor prognosis. Both myo sin cycling and calcium binding to troponin are abnormal in the presence of the mutant tropomyosin. The genetic diagnosis afforded by this mutation wi ll be valuable in the management of HCM.