TNNT2 – Hypertrophic Cardiomyopathy

Cardiac troponin T (TNNT2) is a thin‐filament regulatory protein essential for calcium‐dependent control of myocardial contraction. Autosomal dominant mutations in TNNT2 cause hypertrophic cardiomyopathy (Hypertrophic cardiomyopathy), marked by asymmetric left ventricular hypertrophy, diastolic dysfunction, and increased risk of sudden cardiac death.

HCM due to TNNT2 displays autosomal dominant inheritance with incomplete penetrance. The prototypical Arg92Trp mutation (c.304C>T (p.Arg102Trp)) segregates with disease across two pedigrees, affecting 19 additional relatives in multiple families (PMID:9060892). Segregation analyses confirm co-inheritance in both preclinical and overt HCM cases, supporting high pathogenicity.

Clinical series totaling over 100 unrelated probands have identified approximately 40 distinct TNNT2 variants, predominantly missense changes (e.g., c.304C>T (p.Arg102Trp), c.862C>T (p.Arg288Cys)). Many carriers exhibit minimal hypertrophy (mean maximal wall thickness 11 ± 5 mm) yet face elevated rates of sudden death (PMID:9060892). TNNT2 mutations account for 3–5% of HCM cases in large cohorts (PMID:12881443).

Missense variants cluster within residues 90–180 of the TNT1 tropomyosin‐binding domain; no other clear mutation hotspots exist aside from Arg92Trp. Rare splicing defects (e.g., c.508GAGdel) and deep‐intronic variants have been reported, while some proposed “benign” changes (e.g., p.Ser189Phe) may still manifest full clinical expression (PMID:12473556). Founder alleles have emerged in specific populations.

Functional assays demonstrate that HCM‐associated TNNT2 mutants increase thin‐filament Ca2+ sensitivity and prolong activation. The Phe110Ile mutation impairs maximal actomyosin ATPase activation, stabilizing the off‐state (PMID:10529204). iPSC‐derived cardiomyocytes with the c.478_480del (p.Asn160del) variant exhibit impaired calcium decay and relaxation, recapitulating human diastolic dysfunction (PMID:35861968). Homozygous K280N mutation accelerates cross-bridge kinetics and increases energy cost, highlighting a dominant-negative mechanism (PMID:30578328).

Taken together, robust genetic segregation across multi-generational families, extensive variant discovery in diverse cohorts, and concordant functional data establish a definitive association between TNNT2 and HCM. No strong refuting evidence has emerged. TNNT2 genetic testing refines diagnosis, guides family screening, and informs management decisions, including prophylactic defibrillator implantation. Key Take-home: TNNT2 variant analysis is clinically essential for accurate risk stratification in HCM.

References

• Journal of the American College of Cardiology • 1997 • Sudden death due to troponin T mutations. PMID:9060892
• Circulation • 2002 • Prevalence and severity of "benign" mutations in the beta-myosin heavy chain, cardiac troponin T, and alpha-tropomyosin genes in hypertrophic cardiomyopathy. PMID:12473556
• Biochemistry • 1999 • Altered regulatory function of two familial hypertrophic cardiomyopathy troponin T mutants. PMID:10529204
• Circulation. Genomic and precision medicine • 2022 • Human-Induced Pluripotent Stem Cell-Derived Cardiomyocyte Model for TNNT2 ∆160E-Induced Cardiomyopathy PMID:35861968
• The Journal of general physiology • 2019 • The homozygous K280N troponin T mutation alters cross-bridge kinetics and energetics in human HCM. PMID:30578328
• Clinical chemistry • 2003 • Hypertrophic cardiomyopathy: low frequency of mutations in the beta-myosin heavy chain (MYH7) and cardiac troponin T (TNNT2) genes among Spanish patients. PMID:12881443

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