An internal promoter underlies the difference in disease severity between N-and C-terminal truncation mutations of titin in zebrafish

Jun Zou, Diana Tran, Mai Baalbaki, Ling Fung Tang, Annie Poon, Angelo Pelonero, Erron W. Titus, Christiana Yuan, Chenxu Shi, Shruthi Patchava, Elizabeth Halper, Jasmine Garg, Irina Movsesyan, Chaoying Yin, Roland Wu, Lisa D. Wilsbacher, Jiandong Liu, Ronald L. Hager, Shaun R. Coughlin, Martin JinekClive R. Pullinger, John P. Kane, Daniel O. Hart, Pui Yan Kwok, Rahul C. Deo*

*Corresponding author for this work

Research output: Contribution to journalArticle

43 Scopus citations

Abstract

Truncating mutations in the giant sarcomeric protein Titin result in dilated cardiomyopathy and skeletal myopathy. The most severely affected dilated cardiomyopathy 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 and C-terminal regions. Although all exons were constitutive, C-terminal mutations caused severe myopathy whereas Nterminal 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 Nterminal truncations. In addition to its clinical implications, our work may shed light on a longstanding mystery regarding the architecture of the sarcomere.

Original languageEnglish (US)
Article numbere09406
JournaleLife
Volume4
Issue numberOCTOBER2015
DOIs
StatePublished - Oct 16 2015

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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    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. R., ... Deo, R. C. (2015). An internal promoter underlies the difference in disease severity between N-and C-terminal truncation mutations of titin in zebrafish. eLife, 4(OCTOBER2015), [e09406]. https://doi.org/10.7554/eLife.09406