ZFIN ID: ZDB-PUB-151019-11
An internal promoter underlies the difference in disease severity between N- and C-terminal truncation mutations of Titin
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.
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:
  • Animals
  • Cardiomyopathy, Dilated/pathology*
  • Connectin/genetics*
  • Connectin/metabolism
  • Disease Models, Animal
  • Humans
  • Muscular Diseases/pathology*
  • Mutant Proteins/genetics
  • Mutant Proteins/metabolism
  • Promoter Regions, Genetic*
  • Sequence Deletion*
  • Zebrafish
PubMed: 26473617 Full text @ Elife
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.