Tropomyosin–troponin complex in inherited cardiomyopathies

The tropomyosin-troponin complex (TTC) regulates cardiac contractility by controlling cross-bridge attachments to actin filaments based on intracellular Ca2+ levels. TTC consists of tropomyosin (TPM), cardiac troponin-T (cTnT), cardiac troponin-I (cTnI), and cardiac troponin-C (cTnC). Pathogenic variants (mutations) in genes encoding these proteins (TPM1 [TPM], TNNT2 [cTnT], TNNI3 [cTnI], and TNNC1 [cTnC]) cause different cardiomyopathy types, including hypertrophic (HCM), dilated (DCM), or restrictive cardiomyopathy (RCM).1Arbelo E. Protonotarios A. Gimeno J.R. et al.2023 ESC Guidelines for the management of cardiomyopathies.Eur Heart J. 2023; 44: 3503-3626Crossref PubMed Scopus (99) Google Scholar Currently, an overview of mutations in TTC-encoding genes and associated phenotypes is lacking and it is unknown if genotype-phenotype correlations exist between mutation type or location and disease manifestation or severity. Identifying such correlations may enable more patient-tailored management strategies. In this study, we aimed to provide a first detailed overview and analysis of (likely-)pathogenic (LP/P) variants in TTC-encoding genes. We performed a literature review and retrospective cohort study to include patients with these variants reported in the literature and seen at our center. The latter provided informed consent and the study received institutional review board approval. We included patients with available clinical, genetic, and imaging data for assessing disease penetrance and genotype-phenotype correlations, and used Chi-square or ANOVA tests for statistical analysis. We found 141 unique LP/P-variants in 843 subjects, with phenotypic data available for 794 subjects (Figure 1A). LP/P-variants in TPM1 were more often associated with HCM than other TCC-encoding genes (P<0.001), while TNNC1-variants were more frequently linked to DCM (P<0.0001). We also found an association between mutation topology and phenotype (Figure 1B). All variants in TPM-C-terminus were linked to HCM. Variants in cTnI-inhibitory domain were more often associated with HCM than variants in other cTnI domains (P=0.011), while variants in cTnI-C-terminus were more often linked to RCM (P=0.0003). Interestingly, variants in cTnI-N-terminus were more often identified in asymptomatic carriers than variants in other cTnI domains (P=0.0017). As most variants were missense (N=136), we found no association between mutation type and phenotype. Regarding disease severity in HCM patients, TPM1-variants were associated with more myocardial hypertrophy than other gene variants, whereas TNNT2-variants showed the lowest extent of hypertrophy (interventricular septum 20±3mm vs. 16±3mm; P<0.001). However, TNNT2-variants had the highest prevalence of SCD, which was the lowest for TNNI3 (24.0±2.7% vs. 9.8±1.7, respectively; P<0.001). We found no differences in LV dimensions/function among TTC-encoding genes in DCM patients. Intriguingly, our findings resonate with a tension-based model postulating that mutations augmenting tension within sarcomeres tend to result in HCM, while those diminishing tension are inclined towards DCM.2Davis J. Davis L.C. Correll R.N. et al.A tension-based model distinguishes hypertrophic versus dilated cardiomyopathy.Cell. 2016; 165: 1147-1159Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar DCM- and HCM associated variants correspond with previously reported decrease or increase in myofilament Ca2+-sensitivity, respectively (Figure 1C), except for the cTnT-Arg141Trp variant, suggesting that specific sarcomere gene mutations modify the cardiomyopathic phenotype by modulating sarcomeric tension. In conclusion, we found that TPM1-variants are more linked to HCM, while TNNC1-variants are more common in DCM. We observed an association between variant location and phenotype, with variants in TPM-C-terminus and cTnI-inhibitory domain more often causing HCM, and variants in cTnI-C-terminus leading to RCM. Additionally, our results indicate varying disease severity among TTC-encoding genes, with TPM1-variants causing more severe HCM, and TNNT2-variants more linked to SCD but less pronounced hypertrophy. Our findings can enhance genetic counselling, enable patient-tailored diagnostic strategies, and improve SCD prediction algorithms.