Key result
Truncated titin integrates into sarcomeres in TTN-mutant DCM, pointing to structural defects over haploinsufficiency.
Why the study?
Heterozygous truncating mutations in the TTN gene are the most common genetic cause of DCM, but the molecular mechanisms by which they induce DCM remain controversial.
Observational (n=127)
Blinding of the investigator was applied in the case of the analysis of the super-resolution microscopy images
Sample randomization applied in super-resolution microscopy image analysis
No
This study demonstrates that truncated titin incorporates structurally into human cardiac sarcomeres, suggesting that structural defects and faulty mechanosensing drive TTNtv-mediated dilated cardiomyopathy rather than haploinsufficiency alone.
Structural titin defects may drive TTNtv DCM; leaves open targeted therapies pending prospective validation.
Heterozygous (HET) truncating mutations in the TTN gene (TTNtv) 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 investigated 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. The total amount of expressed titin, which includes the truncated fragments, was comparable in the TTNtv+ and TTNtv-samples, indicating that titin haploinsufficiency is not the leading cause of the molecular pathogenesis. Proteomic analysis of washed cardiac myofibrils and Stimulated Emission Depletion (STED) super-resolution microscopy of myocardial sarcomeres labeled with sequence-specific anti-titin antibodies revealed that truncated titin is structurally integrated in the sarcomere. Sarcomere lengthdependent anti-titin epitope position, shape and intensity analysis pointed at structural defects in the I/A junction and the M-band of TTNtv+ sarcomeres, which may contribute, via faulty mechanosensor function, to the development of manifest DCM.
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Kellermayer et al. (2023) conducted an observational in Dilated cardiomyopathy (DCM) (n=127). Titin truncating variants (TTNtv) vs. DCM samples without titin truncating variants was evaluated on Sarcomeric integration of truncated titin and structural defects. In 127 end-stage dilated cardiomyopathy patients, truncated titin was structurally integrated into the sarcomeres of those with TTN mutations, indicating structural defects over haploinsufficiency.
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