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The effect of tropomyosin variants on cardiomyocyte function and structure that underlie different clinical

Larissa M Dorsch1, Diederik W D Kuster1, Jan D H Jongbloed2

  • 1Department of Physiology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands.

International Journal of Cardiology
|September 4, 2020
PubMed

Insights

Genetic variants in the alpha-tropomyosin gene (TPM1) disrupt cardiomyocyte calcium handling and sarcomeric structure, leading to various cardiomyopathies like dilated (DCM) and hypertrophic (HCM) forms.

Area of Science:

  • Cardiovascular Genetics
  • Molecular Cardiology
  • Cellular Physiology

Background:

  • Alpha-tropomyosin gene (TPM1) variants are linked to inherited cardiomyopathies, including dilated (DCM), hypertrophic (HCM), and restrictive (RCM) types.
  • Distinct TPM1 variants may differentially impact cardiomyocyte function, contributing to varied clinical presentations.

Purpose of the Study:

  • To investigate the differential effects of TPM1 variants (T201M, E62Q, M281T) on cardiomyocyte physiology.
  • To correlate specific TPM1 variants with distinct cardiomyopathy phenotypes (DCM, HCM, RCM).

Main Methods:

  • Studied the impact of TPM1 variants on single-cell calcium transients (CaT) in HL-1 cardiomyocytes via dose-dependent transfection.
  • Analyzed cardiomyocyte structure in human cardiac biopsies from patients with TPM1 variants.
  • Assessed the replacement of endogenous tropomyosin by variant TPM1 proteins.

Main Results:

  • TPM1 variant overexpression progressively impaired CaT, with varying severity (E62Q < T201M ≈ M281T).
  • Compound heterozygote E62Q/M281T did not worsen effects compared to single variants.
  • T201M (DCM) dose-dependently replaced endogenous tropomyosin, unlike M281T (HCM).
  • Human cardiac biopsies showed sarcomeric structure loss in TPM1 variant carriers.

Conclusions:

  • All studied TPM1 variants reduce cardiomyocyte CaT amplitudes and disrupt sarcomeric integrity.
  • These cellular defects are potential mechanisms underlying the diverse cardiomyopathy phenotypes associated with TPM1 mutations.

Keywords:
Calcium transientsCardiomyopathyHuman tissueTPM1Thin filamentsTropomyosin

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