TNNT2 – Cardiomyopathy

Cardiac troponin T, encoded by TNNT2, is a key thin-filament regulatory protein essential for calcium-mediated sarcomere activation and cardiac contractility. Pathogenic TNNT2 variants have been implicated in a spectrum of cardiomyopathy phenotypes, including hypertrophic (HCM), dilated (DCM) and left ventricular non-compaction cardiomyopathies (LVNC), typically with autosomal dominant inheritance and age-dependent penetrance.

Genetic evidence for TNNT2 in cardiomyopathy is robust: a recent meta-analysis identified TNNT2 variants in 224 unrelated probands across HCM, DCM and LVNC cohorts ([PMID:32278834]). The variant spectrum is dominated by missense substitutions and in-frame deletions clustering in the tropomyosin-binding region, with fewer splice-site and deep-intronic alleles. Population databases show these variants are rare or absent in controls, consistent with high penetrance in affected families.

Segregation data further support causality. A novel missense change, c.316G>A (p.Glu106Lys), was identified in an LVNC-affected pedigree, co-segregating with disease in all affected relatives and absent in 430 controls ([PMID:20083571]), yielding segregation in seven family members.

Functional studies corroborate a dominant-negative mechanism. Gene-targeted mice heterozygous for the human TNNT2 p.Arg141Trp (R141W) mutation develop DCM with left ventricular dilation, reduced contractility, and calcium desensitization; phenotype severity is gene dosage dependent ([PMID:27936050]). In the zebrafish silent heart model, tnnt2 loss leads to severe sarcomere defects and impaired cardiac contractility, underscoring its essential role in sarcomere assembly ([PMID:11967535]).

In vitro biochemical assays of DCM-associated TNNT2 mutations demonstrate consistent reductions in Ca2+ sensitivity of regulated thin filaments, paralleling clinical DCM physiology ([PMID:15923195]). These findings establish a unifying mechanism opposite to HCM-causing TNNT2 alleles, which increase Ca2+ sensitivity.

Taken together, the genetic, segregation and functional data support a Strong clinical validity classification for TNNT2 in autosomal dominant cardiomyopathy. Routine inclusion of TNNT2 in cardiomyopathy gene panels enables precise molecular diagnosis, informs risk assessment, and guides family screening.

References

• Journal of molecular and cellular cardiology • 2020 • Meta-analysis of cardiomyopathy-associated variants in troponin genes identifies loci and intragenic hot spots that are associated with worse clinical outcomes. PMID:32278834
• Cardiovascular research • 2010 • Severe familial left ventricular non-compaction cardiomyopathy due to a novel troponin T (TNNT2) mutation. PMID:20083571
• Nature genetics • 2002 • Cardiac troponin T is essential in sarcomere assembly and cardiac contractility. PMID:11967535
• PloS one • 2016 • Gene-Targeted Mice with the Human Troponin T R141W Mutation Develop Dilated Cardiomyopathy with Calcium Desensitization. PMID:27936050
• The Journal of biological chemistry • 2005 • Dilated cardiomyopathy mutations in three thin filament regulatory proteins result in a common functional phenotype. PMID:15923195

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