Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM), the most common cause of sudden death in the young, is an autosomal dominant disease characterized by ventricular hypertrophy accompanied by myofibrillar disarrays1. Linkage studies and candidate-gene approaches have demonstrated that about half of the patients have mutations in one of six disease genes: cardiac (β-myosin heavy chain (cβMHQ2,3) cardiac troponin T (cThT)4,5, α-tropomyosin (αTM)5'6, cardiac myosin binding protein C (cMBP-C)7–9, ventricular myosin essential light chain (vMLC1)10 and ventricular myosin regulatory light chain (vMLC2)10 genes. Other disease genes remain unknown. Because all the known disease genes encode major contractile elements in cardiac muscle11, we have systematically characterized the cardiac sarcomere genes, including cardiac troponin I (cTnl), cardiac actin (cACT) and cardiac troponin C (cTnC)12 in 184 unrelated patients with HCM and found mutations in the cTnl gene in several patients13. Family studies showed that an Arg145Gly mutation was linked to HCM and a Lys206Gln mutation had occurred de novo, thus strongly suggesting that cTnl is the seventh HCM gene.