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 disarrays. Linkage studies and candidate-gene approaches have demonstrated that about half of the patients have mutations in one of six disease genes: cardiac beta-myosin heavy chain (c beta MHC), cardiac troponin T (cTnT), alpha-tropomyosin (alpha TM), cardiac myosin binding protein C (cMBPC), ventricular myosin essential light chain (vMLC1) and ventricular myosin regulatory light chain (vMLC2) genes. Other disease genes remain unknown. Because all the known disease genes encode major contractile elements in cardiac muscle, we have systematically characterized the cardiac sarcomere genes, including cardiac troponin I (cTnI), cardiac actin (cACT) and cardiac troponin C (cTnC) in 184 unrelated patients with HCM and found mutations in the cTnI gene in several patients. Family studies showed that an Arg145Gly mutation was linked to HCM and a Lys206Gln mutation had occurred de novo, thus strongly suggesting that cTnI is the seventh HCM gene.

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Idiopathic dilated cardiomyopathy (IDC) is characterized by a thin-walled heart with systolic dysfunction of unknown etiology. Because abnormalities in genes for cytoskeletal proteins related to Z-disc function have recently been reported to cause IDC, genomic organization of the gene for nebulette, a novel actin-binding Z-disc protein, was determined and its sequence variations were searched for in Japanese patients with IDC and healthy controls. The nebulette gene consists of 28 exons, and four sequence variations leading to amino acid replacement (Gln187His, Met351Val, Asn654Lys, and Thr728Ala) were identified in the patients. These variations were also found in the healthy controls and hence they were polymorphisms and not disease-specific mutations. Frequencies of Gln187His, Met351Val, and Thr728Ala variants were similar in the patients and controls. However, the frequency of homozygotes for Lys at codon 654, a variant at a relatively conserved residue in an actinbinding motif, was significantly increased in nonfamilial IDC patients (n=106) as compared with healthy control subjects (n=331) (7.54% vs 1.21%, OR=6.25, P=0.002, 95% CI=1.92-20.29), while this association was not found in familial IDC patients (n=24). These observations suggest that the nebulette polymorphism in the actin-binding motif was a novel genetic marker of susceptibility to nonfamilial IDC.