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 - du Marchie Sarvaas, Gideon J
AU - van den Berg, Maarten P
AU - van der Velden, Jolanda
AU - Brundel, Bianca J J M
AU - van der Zwaag, Paul A
N1 - Funding Information:
Acknowledgement of grant support: This work was supported by the Netherlands Cardiovascular Research Initiative: An initiative with support of the Dutch Heart Foundation [grant numbers CVON2014-40 DOSIS, CVON- STW2016-14728 AFFIP] and Netherlands Organization for Sciences (NWO)-ZonMW [grant number VICI 91818602].
Publisher Copyright:
© 2020 The Authors
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.
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.
KW - Calcium transients
KW - Cardiomyopathy
KW - Human tissue
KW - Thin filaments
KW - TPM1
KW - Tropomyosin
UR - http://www.scopus.com/inward/record.url?scp=85090830185&partnerID=8YFLogxK
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 -