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- Title
Truncated titin proteins and titin haploinsufficiency are targets for functional recovery in human cardiomyopathy due to TTN mutations.
- Authors
Fomin, Andrey; Gärtner, Anna; Cyganek, Lukas; Tiburcy, Malte; Tuleta, Izabela; Wellers, Luisa; Folsche, Lina; Hobbach, Anastasia J.; von Frieling-Salewsky, Marion; Unger, Andreas; Hucke, Anna; Koser, Franziska; Kassner, Astrid; Sielemann, Katharina; Streckfuß-Bömeke, Katrin; Hasenfuss, Gerd; Goedel, Alexander; Laugwitz, Karl-Ludwig; Moretti, Alessandra; Gummert, Jan F.
- Abstract
Tracking titin in dilated cardiomyopathy: Truncating variants in TTN, the gene encoding the titin protein, underlie 15 to 25% of cases of nonischemic dilated cardiomyopathy (DCM), but whether the disease is caused by haploinsufficiency or the presence of truncated titin proteins is not yet clear. Here, using tissues from the hearts of patients with DCM and TTN truncating variants as well as human induced pluripotent stem cells differentiated into cardiomyocytes, Fomin et al. and McAfee et al. identified both the presence of truncated titin proteins and less-abundant full-length titin proteins. These findings suggest that the presence of truncated titin proteins as "poison peptides" and titin haploinsufficiency both contribute to the pathogenesis of disease and should support the investigation of targeted therapies to treat DCM caused by TTN truncating variants. Heterozygous truncating variants in TTN (TTNtv), the gene coding for titin, cause dilated cardiomyopathy (DCM), but the underlying pathomechanisms are unclear and disease management remains uncertain. Truncated titin proteins have not yet been considered as a contributor to disease development. Here, we studied myocardial tissues from nonfailing donor hearts and 113 patients with end-stage DCM for titin expression and identified a TTNtv in 22 patients with DCM (19.5%). We directly demonstrate titin haploinsufficiency in TTNtv-DCM hearts and the absence of compensatory changes in the alternative titin isoform Cronos. Twenty-one TTNtv-DCM hearts in our cohort showed stable expression of truncated titin proteins. Expression was variable, up to half of the total titin protein pool, and negatively correlated with patient age at heart transplantation. Truncated titin proteins were not detected in sarcomeres but were present in intracellular aggregates, with deregulated ubiquitin-dependent protein quality control. We produced human induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs), comparing wild-type controls to cells with a patient-derived, prototypical A-band-TTNtv or a CRISPR-Cas9–generated M-band-TTNtv. TTNtv-hiPSC-CMs showed reduced wild-type titin expression and contained truncated titin proteins whose proportion increased upon inhibition of proteasomal activity. In engineered heart muscle generated from hiPSC-CMs, depressed contractility caused by TTNtv could be reversed by correction of the mutation using CRISPR-Cas9, eliminating truncated titin proteins and raising wild-type titin content. Functional improvement also occurred when wild-type titin protein content was increased by proteasome inhibition. Our findings reveal the major pathomechanisms of TTNtv-DCM and can be exploited for new therapies to treat TTNtv-related cardiomyopathies.
- Subjects
CONNECTIN; INDUCED pluripotent stem cells; MYOCARDIUM; GENETIC variation; PROTEINS; DILATED cardiomyopathy
- Publication
Science Translational Medicine, 2021, Vol 13, Issue 618, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.abd3079