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Truncated titin is structurally integrated into the human dilated cardiomyopathic sarcomere
Dalma Kellermayer, … , Béla Merkely, Miklós S.Z. Kellermayer
Dalma Kellermayer, … , Béla Merkely, Miklós S.Z. Kellermayer
Published November 14, 2023
Citation Information: J Clin Invest. 2024;134(2):e169753. https://doi.org/10.1172/JCI169753.
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Research Article Cardiology Muscle biology Article has an altmetric score of 2

Truncated titin is structurally integrated into the human dilated cardiomyopathic sarcomere

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Abstract

Heterozygous (HET) truncating variant mutations in the TTN gene (TTNtvs), encoding the giant titin protein, are the most common genetic cause of dilated cardiomyopathy (DCM). However, the molecular mechanisms by which TTNtv mutations induce DCM are controversial. Here, we studied 127 clinically identified DCM human cardiac samples with next-generation sequencing (NGS), high-resolution gel electrophoresis, Western blot analysis, and super-resolution microscopy in order to dissect the structural and functional consequences of TTNtv mutations. The occurrence of TTNtv was found to be 15% in the DCM cohort. Truncated titin proteins matching, by molecular weight, the gene sequence predictions were detected in the majority of the TTNtv+ samples. Full-length titin was reduced in TTNtv+ compared with TTNtv– samples. Proteomics analysis of washed myofibrils and stimulated emission depletion (STED) super-resolution microscopy of myocardial sarcomeres labeled with sequence-specific anti-titin antibodies revealed that truncated titin was structurally integrated into the sarcomere. Sarcomere length–dependent anti–titin epitope position, shape, and intensity analyses pointed at possible structural defects in the I/A junction and the M-band of TTNtv+ sarcomeres, which probably contribute, possibly via faulty mechanosensor function, to the development of manifest DCM.

Authors

Dalma Kellermayer, Hedvig Tordai, Balázs Kiss, György Török, Dániel M. Péter, Alex Ali Sayour, Miklós Pólos, István Hartyánszky, Bálint Szilveszter, Siegfried Labeit, Ambrus Gángó, Gábor Bedics, Csaba Bödör, Tamás Radovits, Béla Merkely, Miklós S.Z. Kellermayer

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Figure 4

Skinned and washed myofibrils contain the truncated titin protein.

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Skinned and washed myofibrils contain the truncated titin protein.
SDS-P...
SDS-PAGE electrophoretogram of washed myofibril (myofib) pellets solubilized in urea buffer at 1:3 and 1:10 ratios. In contrast to the TTNtv– sample (patient 7), the TTNtv+ myofibril sample (patient 75) contained truncated titin, suggesting that the truncated protein was part of the sarcomere (see also Supplemental Figure 2A). In further support of this observation, the concentrated supernatants of the washed and centrifuged myofibril samples were devoid of detectable amounts of truncated titin (Supplemental Figure 2B). The gel image shown here is a spliced duplicate of the full gel shown in Supplemental Figure 2A. The dotted line indicates the splice. Red arrowheads point at truncated titin.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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