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Genotype-specific pathogenic effects in human dilated cardiomyopathy.

Title: Genotype-specific pathogenic effects in human dilated cardiomyopathy.
Name(s): Bollen, Ilse A E, author
Schuldt, Maike, author
Harakalova, Magdalena, author
Vink, Aryan, author
Asselbergs, Folkert W, author
Pinto, Jose R, author
Krüger, Martina, author
Kuster, Diederik W D, author
van der Velden, Jolanda, author
Type of Resource: text
Genre: Journal Article
Date Issued: 2017-07-15
Physical Form: computer
online resource
Extent: 1 online resource
Language(s): English
Abstract/Description: Mutations in genes encoding cardiac troponin I (TNNI3) and cardiac troponin T (TNNT2) caused altered troponin protein stoichiometry in patients with dilated cardiomyopathy. TNNI3p.98trunc resulted in haploinsufficiency, increased Ca(2+) -sensitivity and reduced length-dependent activation. TNNT2p.K217del caused increased passive tension. A mutation in the gene encoding Lamin A/C (LMNAp.R331Q ) led to reduced maximal force development through secondary disease remodelling in patients suffering from dilated cardiomyopathy. Our study shows that different gene mutations induce dilated cardiomyopathy via diverse cellular pathways. 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 Ca(2+) -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.
Identifier: FSU_pmch_28436080 (IID), 10.1113/JP274145 (DOI), PMC5509872 (PMCID), 28436080 (RID), 28436080 (EID)
Keywords: Dilated cardiomyopathy, Heart failure, Protein phosphorylation, Troponin
Publication Note: This NIH-funded author manuscript originally appeared in PubMed Central at
Persistent Link to This Record:
Owner Institution: FSU
Is Part Of: The Journal of physiology.
Issue: iss. 14, vol. 595

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Bollen, I. A. E., Schuldt, M., Harakalova, M., Vink, A., Asselbergs, F. W., Pinto, J. R., … Van der Velden, J. (2017). Genotype-specific pathogenic effects in human dilated cardiomyopathy. The Journal Of Physiology. Retrieved from