PUBLICATION
Location-Dependent Differences in Cardiac and Skeletal Muscle Dysfunction Associated With Truncating Titin (ttn.2) Variants
- Authors
- Santiago, C.F., Huttner, I.G., Brien, A.O., Amerudin, M.A.B., Bennett, P.M., Cvetkovska, J., Chand, R., Holt, M., Trivedi, G., Wang, L.W., Yang, X., Smith, K.A., Gautel, M., Fatkin, D., Hinits, Y.
- ID
- ZDB-PUB-260107-16
- Date
- 2026
- Source
- Circulation research : (Journal)
- Registered Authors
- Chand, Renee, Fatkin, Diane, Hinits, Yaniv, Huttner, Inken, Trivedi, Gunjan
- Keywords
- echocardiography, epinephrine, proteomics, sarcomeres, zebrafish
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Connectin*/genetics
- Connectin*/metabolism
- Heart*/embryology
- Heart*/physiopathology
- Humans
- Muscle, Skeletal*/metabolism
- Muscle, Skeletal*/physiopathology
- Mutation
- Myocardium*/metabolism
- Myocardium*/pathology
- Phenotype
- Sarcomeres/metabolism
- Zebrafish/genetics
- Zebrafish Proteins*/genetics
- Zebrafish Proteins*/metabolism
- PubMed
- 41498146 Full text @ Circ. Res.
Citation
Santiago, C.F., Huttner, I.G., Brien, A.O., Amerudin, M.A.B., Bennett, P.M., Cvetkovska, J., Chand, R., Holt, M., Trivedi, G., Wang, L.W., Yang, X., Smith, K.A., Gautel, M., Fatkin, D., Hinits, Y. (2026) Location-Dependent Differences in Cardiac and Skeletal Muscle Dysfunction Associated With Truncating Titin (ttn.2) Variants. Circulation research. :.
Abstract
Background Truncating variants in the TTN gene (TTNtv), 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 6 zebrafish lines carrying truncating ttn.2 variants in the Z-disk, I-band, A-band, and M-band titin regions. Expression of titin transcripts and protein levels was evaluated using quantitative polymerase chain reaction and proteomics. Phenotype analysis was performed during embryonic development and in adult hearts.
Results Homozygous embryos from all lines except the C-terminal line, e232, showed a significant reduction of Z-disk and I-band ttn.2 transcripts, but A-band and M-band transcript levels were reduced only in lines with truncations distal to the cronos promoter. These homozygous embryos uniformly died by 7 to 10 days postfertilization 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 with those proximal. In contrast, homozygous e232 embryos, which lacked only the titin kinase and M-band regions, had relatively preserved cardiac function with incorporation of truncated Ttn.2/Cronos protein and normal sarcomere assembly, but selective degradation of fast skeletal muscle sarcomeres. All 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 requirements for C-terminal titin for maintenance of fast, slow, and cardiac muscle sarcomeres.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping