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Abstract: Background. – Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disorder caused by mutations in sarcomeric proteins. Cardiac troponin I (cTnI) is a key switch molecule in the sarcomere. Mutations in cTnI have been identified in <1% of genotyped HCM families. Methods. – To study the prevalence, clinical significance and functional consequences of cTnI mutations, genetic testing was performed in 120 consecutive Australian families with HCM referred to a tertiary referral centre, and results correlated with clinical phenotype. Each cTnI mutation identified was tested in a mammalian two-hybrid system to evaluate the functional effects of these mutations on troponin complex interactions. Results. – Disease-causing missense mutations were identified in four families (3.3%). Two mutations were located at the same codon in exon 7 (R162G, R162P), and two in exon 8 (L198P, R204H). All four mutations change amino acid residues which are highly conserved and were not found in normal populations. Follow-up family screening has identified a total of seven clinically affected members in these four families, with a further four members who carry the gene mutation but have no clinical evidence of disease. Age at clinical presentation was variable (range 15–68 years) and the mean septal wall thickness was 19.3 ± 4.6 mm (range 7–33 mm) in clinically affected individuals, including children. In all four families, at least one member had a sudden cardiac death event, including previous cardiac arrest, indicating a more malignant form of HCM. All four mutations disrupted functional interactions with troponin C and T and this may account for the increased severity of disease in these families. Conclusions. – Gene mutations in cTnI occur in Australian families with HCM with a prevalence higher than previously reported and may be associated with a clinically more malignant course, reflecting significant disruptions to troponin complex interactions. [Copyright &y& Elsevier]

Hypertrophic cardiomyopathy (HCM) is a disorder which has fascinated clinicians for many years. The remarkable diversity in clinical presentations, ranging from no symptoms to severe heart failure and sudden cardiac death, illustrates the complexity of this disorder. Over the last decade, major advances have been made in our understanding of the molecular basis of several cardiac conditions. HCM was the first cardiac disorder in which a genetic basis was identified and as such, has acted as a paradigm for the study of an inherited cardiac disorder. At least eleven genes have now been identified, defects in which cause HCM. Most of these genes encode proteins which comprise the basic contractile unit of the heart, i.e. the sarcomere. Genetic studies are now beginning to have a major impact on diagnosis in HCM, as well as in guiding treatment and preventative strategies. While much is known about which genes cause disease, relatively little is known about the molecular steps leading from the gene defect to the clinical phenotype, and what factors modify the expression of the mutant genes. Concurrent studies in cell culture and animal models of HCM are now beginning to shed light on the signalling pathways involved in HCM, and the role of both environmental and genetic modifying factors. Understanding these basic molecular mechanisms will ultimately improve our knowledge of the basic biology of heart muscle function, and will therefore provide new avenues for diagnosis and treatment not only for HCM, but for a range of cardiovascular diseases in man. [Copyright &y& Elsevier]

Abstract: Gene mutations in cardiac troponin I (cTnI) account for up to 5% of genotyped families with familial hypertrophic cardiomyopathy (FHC). Little is known about how cTnI mutations cause disease. Five lines of transgenic mice were generated which overexpress the human disease-causing cTnI gene mutation, Gly203Ser (designated cTnI-G203S), in a cardiac-specific manner. Mice were compared to transgenic mice that overexpress normal cTnI (cTnI-wt) and non-transgenic littermates (NTG). cTnI-G203S mice developed all the characteristic features of FHC by age 21 weeks. Left ventricular hypertrophy was observed on echocardiography (1.25±0.05 mm vs. 0.86±0.02 mm in cTnI-wt, P <0.01), associated with a significant 4-fold increase in RNA markers of hypertrophy, ANF and BNP. Myocyte hypertrophy, myofiber disarray and interstitial fibrosis were observed in cTnI-G203S mice. Expression of the cTnI-G203S mutation in neonatal cardiomyocytes resulted in a significant increase in myocyte volume, and reduced interactions with both troponins T and C. Ca2+ cycling was abnormal in adult cardiomyocytes extracted from cTnI-G203S mice, with a prolonged decay constant in Ca2+ transients and a reduced decay constant in response to caffeine treatment. Mice with the cTnI-G203S gene mutation develop all the phenotypic features of human FHC. The cTnI-G203S mutation disrupts interactions with partner proteins, and results in intracellular Ca2+ dysregulation early in life, suggesting a pathogenic role in development of FHC. [Copyright &y& Elsevier]