C-terminal Titin truncations caused severe myopathy whereas N-terminal mutations demonstrated mild phenotypes, explained by a conserved internal promoter that partially rescues N-terminal truncations.
Does the position of Titin truncation mutations (N- vs C-terminal) affect disease severity in a zebrafish model?
The difference in disease severity between N- and C-terminal Titin truncation mutations is driven by a conserved internal promoter that partially rescues N-terminal truncations.
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 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.
Zou et al. (Fri,) conducted a other in Dilated cardiomyopathy and skeletal myopathy. Titin truncations in the N-terminal and C-terminal regions vs. N-terminal vs C-terminal mutations was evaluated on Disease severity and myopathy phenotype. C-terminal Titin truncations caused severe myopathy whereas N-terminal mutations demonstrated mild phenotypes, explained by a conserved internal promoter that partially rescues N-terminal truncations.
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