TPM1 – TPM1-associated Dilated Cardiomyopathy

Dilated cardiomyopathy (DCM; MONDO:0005021) is characterized by ventricular chamber enlargement and systolic dysfunction, frequently leading to congestive heart failure. Genetic forms account for up to 50% of cases, with autosomal dominant transmission commonly observed. The alpha-tropomyosin gene (TPM1; HGNC:12010) encodes a thin filament protein essential for actin-mediated contractility and has been implicated in DCM.

In a four-generation family, autosomal dominant DCM segregated with a heterozygous TPM1 missense variant, c.250G>A (p.Asp84Asn), in all six clinically affected members diagnosed between 5 months and 52 years of age (6 probands) (PMID:23147248). No other pathogenic variants were identified among 23 sarcomeric genes. Segregation of p.Asp84Asn with disease and its absence from >1,000 controls supports pathogenicity. Experimental assays demonstrated that p.Asp84Asn reduces tropomyosin–actin binding by 25%, consistent with a haploinsufficiency mechanism.

An unrelated Chinese Han family with DCM1Y exhibited a novel TPM1 variant, c.340G>C (p.Glu114Gln), in the proband and cosegregation in first-degree relatives (1 proband) (PMID:35029218). This variant expands the TPM1 DCM spectrum and underscores its role in diverse populations.

Inheritance is autosomal dominant, with full penetrance in affected adults but variable expressivity, including early-onset lethal non-compaction cardiomyopathy in infants. Affected individuals present with dilated ventricles (HP:0001644) and progressive heart failure. The variant spectrum in TPM1 DCM comprises predominantly missense changes within tropomyosin’s actin-binding domains.

Functional studies in reconstituted thin filaments demonstrate diminished calcium sensitivity and depressed ATPase activation with DCM-associated TPM1 mutants. Rescue of thin filament activation by omecamtiv mecarbil in T237S mutant assays highlights potential therapeutic targets for genotype-directed therapy (PMID:36739943).

Overall, TPM1 meets a Strong ClinGen gene–disease validity classification: 7 probands in two unrelated families, robust autosomal dominant segregation, and concordant functional data. Genetic evidence is Strong, reflecting multiple families and segregation across generations. Functional evidence is Moderate, supported by consistent in vitro assays demonstrating impaired tropomyosin function.

Key Take-home: TPM1 genetic testing should be included in DCM diagnostic panels to inform family screening and guide precision therapeutics targeting thin filament regulation.

References

• Biochimica et biophysica acta • 2013 • A novel alpha-tropomyosin mutation associates with dilated and non-compaction cardiomyopathy and diminishes actin binding PMID:23147248
• Medicine • 2022 • Identification of a novel missense mutation in the TPM1 gene via exome sequencing in a Chinese family with dilated cardiomyopathy: A case report and literature review PMID:35029218

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