Key result
Truncating ttn.2 variant location influences distinct cardiac and skeletal muscle dysfunction phenotypes in zebrafish.
Why the study?
Truncating variants in TTN cause diverse cardiac and skeletal muscle disorders, but the effects of variant location on clinical manifestations remain incompletely understood.
Truncating variants in the ttn.2 gene cause location-dependent cardiac and skeletal muscle dysfunction in a zebrafish model, influenced by age and functional titin protein levels.
Should not yet guide human TTN variant interpretation; leaves open location-specific effects for further model and clinical study.
Background Truncating variants ( TTN tv) in the TTN gene, encoding the giant sarcomeric protein titin, cause a range of human cardiac and skeletal muscle disorders of varying penetrance and severity. The effects of variant location on clinical manifestations are incompletely understood. Methods We generated six zebrafish lines carrying tv in the ttn.2 gene at the Z-disk, I-band, A-band, and M-band titin regions. Expression of titin transcripts was evaluated using qPCR. Phenotype analysis was performed during embryonic development and in adult hearts. Results Using location-specific primers, we found a significant reduction of Z-disk and I-band ttn.2 transcripts in all homozygous embryos but levels of A-band and M-band transcripts were reduced only in lines with truncations distal to the cronos promoter. Homozygous embryos uniformly died by 7-10 days post fertilization with marked impairment of cardiac morphology and function. Skeletal muscle motility and sarcomere organization were more disrupted in mutants with truncations distal to the cronos promoter compared to those proximal. The most C-terminal line (e232), which lacked only the titin kinase and M-band regions, differed from other lines, with homozygous embryos showing incorporation of truncated Ttn.2/Cronos protein and normal sarcomere assembly, but selective degradation of fast skeletal muscle sarcomeres. Heterozygous embryos were phenotypically indistinguishable from wild-type. High-frequency echocardiography in adult heterozygous fish showed reduced ventricular contraction under resting conditions in A-band mutants. Heterozygous Z-disk and I-band mutants had no significant baseline impairment but were unable to augment ventricular contraction in response to acute adrenaline exposure, indicating a lack of cardiac reserve. Conclusions Our data suggest that cardiac and skeletal muscle dysfunction associated with truncating ttn.2 variants is influenced by age, variant location, and the amount of functional titin protein. The distinctive phenotype associated with distal C-terminal truncations may reflect different requirement for C-terminal titin for maintenance of fast, slow and cardiac muscle sarcomeres.
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Santiago et al. (2024) studied Cardiac and skeletal muscle disorders associated with truncating TTN variants. Truncating variants in the ttn.2 gene at different locations vs. Wild-type or other variant locations was evaluated on Cardiac and skeletal muscle dysfunction and phenotype analysis. Cardiac and skeletal muscle dysfunction associated with truncating ttn.2 variants in zebrafish is influenced by variant location, with distal C-terminal truncations showing a distinctive phenotype.
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