PUBLICATION
An internal promoter underlies the difference in disease severity between N- and C-terminal truncation mutations of Titin
- Authors
- Zou, J., Tran, D., Baalbaki, M., Tang, L.F., Poon, A., Pelonero, A., Titus, E.W., Yuan, C., Shi, C., Patchava, S., Halper, E., Garg, J., Movsesyan, I., Yin, C., Wu, R., Wilsbacher, L.D., Liu, J., Hager, R.L., Coughlin, S., Jinek, M., Pullinger, C.R., Kane, J.P., Hart, D.O., Kwok, P.Y., Deo, R.C.
- ID
- ZDB-PUB-151019-11
- Date
- 2015
- Source
- eLIFE 4: e09406 (Journal)
- Registered Authors
- Deo, Rahul C., Garg, Jasmine, Liu, Jiandong, Patchava, Shruthi, Pelonero, Angelo, Shi, Chenxu, Tran, Diana, Yin, Chaoying, Zou, Jun
- Keywords
- human, human biology, medicine, mouse, zebrafish
- MeSH Terms
-
- Cardiomyopathy, Dilated/pathology*
- Mutant Proteins/genetics
- Mutant Proteins/metabolism
- Connectin/genetics*
- Connectin/metabolism
- PubMed
- 26473617 Full text @ Elife
Abstract
Truncating mutations in the giant sarcomeric protein Titin result in dilated cardiomyopathy (DCM) and skeletal myopathy. The most severely affected DCM patients harbor Titin truncations in the C-terminal two-thirds of the protein, suggesting that mutation position might influence disease mechanism. Using CRISPR/Cas9 technology, we generated six zebrafish lines with Titin truncations in the N-terminal (Z-disk and I-band) and C-terminal (A-band) regions. Although all exons were constitutive, C-terminal mutations caused severe myopathy whereas N-terminal mutations demonstrated mild phenotypes. Surprisingly, neither mutation type acted as a dominant negative. Instead, we found a conserved internal promoter at the precise position where divergence in disease severity occurs, with the resulting protein product partially rescuing N-terminal truncations. In addition to its clinical implications, our work may shed light on a long-standing mystery regarding the architecture of the sarcomere.
Genes / Markers
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Phenotype
Mutations / Transgenics
Human Disease / Model
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Fish
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