Bollen, IAE;
Schuldt, M;
Harakalova, M;
Vink, A;
Asselbergs, FW;
Pinto, JR;
Krueger, M;
... van der Velden, J; + view all
(2017)
Genotype-specific pathogenic effects in human dilated cardiomyopathy.
The Journal of Physiology
, 595
(14)
pp. 4677-4693.
10.1113/JP274145.
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Abstract
Dilated cardiomyopathy (DCM) can be caused by mutations in sarcomeric and non-sarcomeric genes. In this study we defined the pathogenic effects of three DCM-causing mutations: the sarcomeric mutations in genes encoding cardiac troponin I (TNNI3p.98truncation) and cardiac troponin T (TNNT2p.K217deletion; also known as the p.K210del) and the non-sarcomeric gene mutation encoding lamin A/C (LMNAp.R331Q). We assessed sarcomeric protein expression and phosphorylation and contractile behaviour in single membrane-permeabilized cardiomyocytes in human left ventricular heart tissue. Exchange with recombinant troponin complex was used to establish the direct pathogenic effects of the mutations in TNNI3 and TNNT2. The TNNI3p.98trunc and TNNT2p.K217del mutation showed reduced expression of troponin I to 39% and 51%, troponin T to 64% and 53%, and troponin C to 73% and 97% of controls, respectively, and altered stoichiometry between the three cardiac troponin subunits. The TNNI3p.98trunc showed pure haploinsufficiency, increased Ca2+-sensitivity and impaired length-dependent activation. The TNNT2p.K217del mutation showed a significant increase in passive tension that was not due to changes in titin isoform composition or phosphorylation. Exchange with wild-type troponin complex corrected troponin protein levels to 83% of controls in the TNNI3p.98trunc sample. Moreover, upon exchange all functional deficits in the TNNI3p.98trunc and TNNT2p.K217del samples were normalized to control values confirming the pathogenic effects of the troponin mutations. The LMNAp.R331Q mutation resulted in reduced maximal force development due to disease remodelling. Our study shows that different gene mutations induce DCM via diverse cellular pathways.
| Type: | Article |
|---|---|
| Title: | Genotype-specific pathogenic effects in human dilated cardiomyopathy |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1113/JP274145 |
| Publisher version: | https://doi.org/10.1113/JP274145 |
| Language: | English |
| Additional information: | © 2017 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Neurosciences, Physiology, Neurosciences & Neurology, Dilated Cardiomyopathy, Heart Failure, Protein Phosphorylation, Troponin, Cardiac Troponin-I, Length-Dependent Activation, Deletion Mutation Delta-K210, Frank-Starling Mechanism, Hypertrophic Cardiomyopathy, Mouse Model, Lamin-A/c, Functional-Characterization, Titin, Phosphorylation |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Health Informatics |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1570507 |
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