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Dilated cardiomyopathy (DCM) is a myocardial disorder characterized by ventricular dilation and systolic dysfunction. TNNC1 encodes cardiac troponin C (cTnC), the Ca2+-binding subunit of the troponin complex essential for excitation–contraction coupling. Rare missense variants in TNNC1 have been identified in both sporadic and familial DCM, implicating disrupted Ca2+ regulation in disease pathogenesis. Here, we summarize genetic and experimental evidence linking TNNC1 to dilated cardiomyopathy.
Trio exome sequencing revealed a de novo heterozygous missense variant c.12C>G (p.Ile4Met) in a pediatric patient with sporadic DCM, resulting in impaired isometric force generation in permeabilized porcine cardiac muscle (PMID:31748410). Germline mosaicism of a second de novo missense variant c.100G>C (p.Gly34Arg) was observed in three siblings presenting with severe infantile DCM and perinatal loss (PMID:36814108).
In a cohort of 312 idiopathic and familial DCM cases, resequencing of TNNC1 identified four rare heterozygous missense variants in four unrelated probands (1.3% of cohort), all absent from control subjects (PMID:20215591). Additionally, one TNNC1 variant was found in a family-based study of 235 idiopathic DCM patients with 100% penetrance among 21 carriers and was associated with adverse outcomes including transplantation and premature mortality (PMID:15542288).
All reported DCM-associated TNNC1 variants are missense substitutions clustered in the N-terminal regulatory domain, including p.Ile4Met, p.Gly34Arg, p.Met103Ile, p.Asp145Glu, and p.Ile148Val. No truncating or splice variants have been described, indicating allelic heterogeneity without apparent founder alleles.
Functional assays using recombinant human cTnC variants reconstituted into skinned porcine papillary muscle and trabeculae consistently demonstrate reduced Ca2+ sensitivity and depressed maximal force generation for DCM-associated substitutions (PMID:21832052, PMID:15923195). These mutations also diminish the modulatory effects of cTnI phosphorylation, indicating altered allosteric coupling within the troponin complex.
Xenopus tropicalis tncn1 knockout recapitulates ventricular dilation and contractile dysfunction, although in vivo rescue with human cTnC variants was unsuccessful, underscoring a critical role for cTnC in cardiac development and function (PMID:32038292). Structural studies reveal tighter cTnT binding and propagated conformational perturbations in cTnC that compromise cross-bridge cycling, consistent with a dominant-negative mechanism (PMID:31748410).
Overall, heterozygous TNNC1 missense variants exhibit autosomal dominant inheritance, de novo occurrence, and familial segregation, with robust functional data demonstrating impaired Ca2+-mediated force regulation. Future studies should define genotype–phenotype correlations and explore targeted therapies to correct troponin dysfunction. Key Take-home: TNNC1 missense variants are clinically actionable in DCM, supporting genetic testing and mechanistic intervention.
Gene–Disease AssociationStrongEight probands across five unrelated families including de novo and familial segregation; concordant functional data Genetic EvidenceStrongEight unrelated DCM probands with heterozygous TNNC1 variants; reached the genetic evidence cap Functional EvidenceModerateMultiple in vitro and animal models consistently demonstrate decreased Ca2+ sensitivity and contractile dysfunction |