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

Larissa M. Dorsch; Diederik W. D. Kuster; Jan D. H. Jongbloed; Ludolf G. Boven; Karin Y. van Spaendonck-Zwarts; Albert J. H. Suurmeijer; Aryan Vink; Gideon J. du Marchie Sarvaas; Maarten P. van den Berg; Jolanda van der Velden; Bianca J. J. M. Brundel; Paul A. Van der Zwaag

doi:10.1016/j.ijcard.2020.08.101

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

Larissa M. Dorsch^*, Diederik W. D. Kuster, Jan D. H. Jongbloed, Ludolf G. Boven, Karin Y. van Spaendonck-Zwarts, Albert J. H. Suurmeijer, Aryan Vink, Gideon J. du Marchie Sarvaas, Maarten P. van den Berg, Jolanda van der Velden, Bianca J. J. M. Brundel, Paul A. Van der Zwaag

^*Corresponding author voor dit werk

Onderzoeksoutput › Academic › peer review

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Background - Variants within the alpha-tropomyosin gene (TPM1) cause dominantly inherited cardiomyopathies, including dilated (DCM), hypertrophic (HCM) and restrictive (RCM) cardiomyopathy. Here we investigated whether TPM1 variants observed in DCM and HCM patients affect cardiomyocyte physiology differently.

Methods - We identified a large family with DCM carrying a recently identified TPM1 gene variant (T201M) and a child with RCM with compound heterozygote TPM1 variants (E62Q and M281T) whose family members carrying single variants show diastolic dysfunction and HCM. The effects of TPM1 variants (T201M, E62Q or M281T) and of a plasmid containing both the E62Q and M281T variants on single-cell Ca2+ transients (CaT) in HL-1 cardiomyocytes were studied. To define toxic threshold levels, we performed dose-dependent transfection of TPM1 variants. In addition, cardiomyocyte structure was studied in human cardiac biopsies with TPM1 variants.

Results - Overexpression of TPM1 variants led to time-dependent progressive deterioration of CaT, with the smallest effect seen for E62Q and larger and similar effects seen for the T201M and M281T variants. Overexpression of E62Q/M281T did not exacerbate the effects seen with overexpression of a single TPM1 variant. T201M (DCM) replaced endogenous tropomyosin dose-dependently, while M281T (HCM) did not. Human cardiac biopsies with TPM1 variants revealed loss of sarcomeric structures.

Conclusion - All TPM1 variants result in reduced cardiomyocyte CaT amplitudes and loss of sarcomeric structures. These effects may underlie pathophysiology of different cardiomyopathy phenotypes. (C) 2020 The Authors. Published by Elsevier B.V.

Originele taal-2	English
Pagina's (van-tot)	251-258
Aantal pagina's	8
Tijdschrift	International Journal of Cardiology
Volume	323
DOI's	https://doi.org/10.1016/j.ijcard.2020.08.101
Status	Published - 15-jan.-2021

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Dorsch, L. M., Kuster, D. W. D., Jongbloed, J. D. H., Boven, L. G., van Spaendonck-Zwarts, K. Y., Suurmeijer, A. J. H., Vink, A., Sarvaas, G. J. D. M., van den Berg, M. P., van der Velden, J., Brundel, B. J. J. M., & Van der Zwaag, P. A. (2021). The effect of tropomyosin variants on cardiomyocyte function and structure that underlie different clinical cardiomyopathy phenotypes. International Journal of Cardiology, 323, 251-258. https://doi.org/10.1016/j.ijcard.2020.08.101

@article{e0a6b199f0ff441fa5957e0e7852dec0,

title = "The effect of tropomyosin variants on cardiomyocyte function and structure that underlie different clinical cardiomyopathy phenotypes",

abstract = "Background - Variants within the alpha-tropomyosin gene (TPM1) cause dominantly inherited cardiomyopathies, including dilated (DCM), hypertrophic (HCM) and restrictive (RCM) cardiomyopathy. Here we investigated whether TPM1 variants observed in DCM and HCM patients affect cardiomyocyte physiology differently.Methods - We identified a large family with DCM carrying a recently identified TPM1 gene variant (T201M) and a child with RCM with compound heterozygote TPM1 variants (E62Q and M281T) whose family members carrying single variants show diastolic dysfunction and HCM. The effects of TPM1 variants (T201M, E62Q or M281T) and of a plasmid containing both the E62Q and M281T variants on single-cell Ca2+ transients (CaT) in HL-1 cardiomyocytes were studied. To define toxic threshold levels, we performed dose-dependent transfection of TPM1 variants. In addition, cardiomyocyte structure was studied in human cardiac biopsies with TPM1 variants.Results - Overexpression of TPM1 variants led to time-dependent progressive deterioration of CaT, with the smallest effect seen for E62Q and larger and similar effects seen for the T201M and M281T variants. Overexpression of E62Q/M281T did not exacerbate the effects seen with overexpression of a single TPM1 variant. T201M (DCM) replaced endogenous tropomyosin dose-dependently, while M281T (HCM) did not. Human cardiac biopsies with TPM1 variants revealed loss of sarcomeric structures.Conclusion - All TPM1 variants result in reduced cardiomyocyte CaT amplitudes and loss of sarcomeric structures. These effects may underlie pathophysiology of different cardiomyopathy phenotypes. (C) 2020 The Authors. Published by Elsevier B.V.",

keywords = "Tropomyosin, TPM1, Cardiomyopathy, Calcium transients, Thin filaments, Human tissue, THIN FILAMENT MUTATIONS, CARDIAC DYSFUNCTION, HEART, CLASSIFICATION, HYPERTROPHY, CARDIOLOGY, STATEMENT, BIOLOGY, MODEL, MICE",

author = "Dorsch, {Larissa M.} and Kuster, {Diederik W. D.} and Jongbloed, {Jan D. H.} and Boven, {Ludolf G.} and {van Spaendonck-Zwarts}, {Karin Y.} and Suurmeijer, {Albert J. H.} and Aryan Vink and Sarvaas, {Gideon J. du Marchie} and {van den Berg}, {Maarten P.} and {van der Velden}, Jolanda and Brundel, {Bianca J. J. M.} and {Van der Zwaag}, {Paul A.}",

year = "2021",

month = jan,

day = "15",

doi = "10.1016/j.ijcard.2020.08.101",

language = "English",

volume = "323",

pages = "251--258",

journal = "International Journal of Cardiology",

issn = "0167-5273",

publisher = "ELSEVIER IRELAND LTD",

}

Dorsch, LM, Kuster, DWD, Jongbloed, JDH , Boven, LG, van Spaendonck-Zwarts, KY, Suurmeijer, AJH, Vink, A, Sarvaas, GJDM, van den Berg, MP, van der Velden, J, Brundel, BJJM & Van der Zwaag, PA 2021, 'The effect of tropomyosin variants on cardiomyocyte function and structure that underlie different clinical cardiomyopathy phenotypes', International Journal of Cardiology, vol. 323, blz. 251-258. https://doi.org/10.1016/j.ijcard.2020.08.101

TY - JOUR

T1 - The effect of tropomyosin variants on cardiomyocyte function and structure that underlie different clinical cardiomyopathy phenotypes

AU - Dorsch, Larissa M.

AU - Kuster, Diederik W. D.

AU - Jongbloed, Jan D. H.

AU - Boven, Ludolf G.

AU - van Spaendonck-Zwarts, Karin Y.

AU - Suurmeijer, Albert J. H.

AU - Vink, Aryan

AU - Sarvaas, Gideon J. du Marchie

AU - van den Berg, Maarten P.

AU - van der Velden, Jolanda

AU - Brundel, Bianca J. J. M.

AU - Van der Zwaag, Paul A.

PY - 2021/1/15

Y1 - 2021/1/15

N2 - Background - Variants within the alpha-tropomyosin gene (TPM1) cause dominantly inherited cardiomyopathies, including dilated (DCM), hypertrophic (HCM) and restrictive (RCM) cardiomyopathy. Here we investigated whether TPM1 variants observed in DCM and HCM patients affect cardiomyocyte physiology differently.Methods - We identified a large family with DCM carrying a recently identified TPM1 gene variant (T201M) and a child with RCM with compound heterozygote TPM1 variants (E62Q and M281T) whose family members carrying single variants show diastolic dysfunction and HCM. The effects of TPM1 variants (T201M, E62Q or M281T) and of a plasmid containing both the E62Q and M281T variants on single-cell Ca2+ transients (CaT) in HL-1 cardiomyocytes were studied. To define toxic threshold levels, we performed dose-dependent transfection of TPM1 variants. In addition, cardiomyocyte structure was studied in human cardiac biopsies with TPM1 variants.Results - Overexpression of TPM1 variants led to time-dependent progressive deterioration of CaT, with the smallest effect seen for E62Q and larger and similar effects seen for the T201M and M281T variants. Overexpression of E62Q/M281T did not exacerbate the effects seen with overexpression of a single TPM1 variant. T201M (DCM) replaced endogenous tropomyosin dose-dependently, while M281T (HCM) did not. Human cardiac biopsies with TPM1 variants revealed loss of sarcomeric structures.Conclusion - All TPM1 variants result in reduced cardiomyocyte CaT amplitudes and loss of sarcomeric structures. These effects may underlie pathophysiology of different cardiomyopathy phenotypes. (C) 2020 The Authors. Published by Elsevier B.V.

AB - Background - Variants within the alpha-tropomyosin gene (TPM1) cause dominantly inherited cardiomyopathies, including dilated (DCM), hypertrophic (HCM) and restrictive (RCM) cardiomyopathy. Here we investigated whether TPM1 variants observed in DCM and HCM patients affect cardiomyocyte physiology differently.Methods - We identified a large family with DCM carrying a recently identified TPM1 gene variant (T201M) and a child with RCM with compound heterozygote TPM1 variants (E62Q and M281T) whose family members carrying single variants show diastolic dysfunction and HCM. The effects of TPM1 variants (T201M, E62Q or M281T) and of a plasmid containing both the E62Q and M281T variants on single-cell Ca2+ transients (CaT) in HL-1 cardiomyocytes were studied. To define toxic threshold levels, we performed dose-dependent transfection of TPM1 variants. In addition, cardiomyocyte structure was studied in human cardiac biopsies with TPM1 variants.Results - Overexpression of TPM1 variants led to time-dependent progressive deterioration of CaT, with the smallest effect seen for E62Q and larger and similar effects seen for the T201M and M281T variants. Overexpression of E62Q/M281T did not exacerbate the effects seen with overexpression of a single TPM1 variant. T201M (DCM) replaced endogenous tropomyosin dose-dependently, while M281T (HCM) did not. Human cardiac biopsies with TPM1 variants revealed loss of sarcomeric structures.Conclusion - All TPM1 variants result in reduced cardiomyocyte CaT amplitudes and loss of sarcomeric structures. These effects may underlie pathophysiology of different cardiomyopathy phenotypes. (C) 2020 The Authors. Published by Elsevier B.V.

KW - Tropomyosin

KW - TPM1

KW - Cardiomyopathy

KW - Calcium transients

KW - Thin filaments

KW - Human tissue

KW - THIN FILAMENT MUTATIONS

KW - CARDIAC DYSFUNCTION

KW - HEART

KW - CLASSIFICATION

KW - HYPERTROPHY

KW - CARDIOLOGY

KW - STATEMENT

KW - BIOLOGY

KW - MODEL

KW - MICE

U2 - 10.1016/j.ijcard.2020.08.101

DO - 10.1016/j.ijcard.2020.08.101

M3 - Article

C2 - 32882290

SN - 0167-5273

VL - 323

SP - 251

EP - 258

JO - International Journal of Cardiology

JF - International Journal of Cardiology

ER -

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

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