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

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 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

SUBMITTER: Zou J 

PROVIDER: S-EPMC4720518 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature