PUBLICATION
Exon- and contraction-dependent functions of titin in sarcomere assembly
- Authors
- Shih, Y.H., Dvornikov, A.V., Zhu, P., Ma, X., Kim, M.J., Ding, Y., Xu, X.
- ID
- ZDB-PUB-161113-4
- Date
- 2016
- Source
- Development (Cambridge, England) 143(24): 4713-4722 (Journal)
- Registered Authors
- Ding, Yonghe, Ma, Xiao, Shih, Yu-huan, Xu, Xiaolei, Zhu, Ping
- Keywords
- Allelic heterogeneity, Sarcomere assembly, TALEN, Titin, Zebrafish
- MeSH Terms
-
- Alleles
- Allelic Imbalance/genetics
- Animals
- Animals, Genetically Modified
- Cardiomyopathy, Dilated/genetics
- Connectin/genetics*
- Connectin/metabolism
- Myofibrils/metabolism*
- Sarcomeres/genetics
- Sarcomeres/metabolism*
- Sequence Deletion/genetics
- Zebrafish/growth & development*
- PubMed
- 27836965 Full text @ Development
Citation
Shih, Y.H., Dvornikov, A.V., Zhu, P., Ma, X., Kim, M.J., Ding, Y., Xu, X. (2016) Exon- and contraction-dependent functions of titin in sarcomere assembly. Development (Cambridge, England). 143(24):4713-4722.
Abstract
Titin-truncating variants (TTNtvs) are the major cause of dilated cardiomyopathy (DCM); however, allelic heterogeneity (TTNtvs in different exons) results in variable phenotypes, and remains a major hurdle for disease diagnosis and therapy. Here, we generated a panel of ttn mutants in zebrafish. Four single deletion mutants in ttn.2 or ttn.1 resulted in four phenotypes and three double ttn.2/ttn.1 mutants exhibited more severe phenotypes in somites. Protein analysis identified ttnxu071 as a near-null mutant and the other six mutants as hypomorphic alleles. Studies of ttnxu071 uncovered a function of titin in guiding the assembly of nascent myofibrils from premyofibrils. By contrast, sarcomeres were assembled in the hypomorphic ttn mutants but either became susceptible to biomechanical stresses such as contraction or degenerated during development. Further genetic studies indicated that the exon usage hypothesis, but not the toxic peptide or the Cronos hypothesis, could account for these exon-dependent effects. In conclusion, we modeled TTNtv allelic heterogeneity during development and paved the way for future studies to decipher allelic heterogeneity in adult DCM.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping