eLife · 2015
An internal promoter underlies the difference in disease severity between N- and C-terminal truncation mutations of Titin in zebrafish.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Zou Jun, Tran Diana, Baalbaki Mai, Tang Ling Fung, Poon Annie, Pelonero Angelo, Titus Erron W, Yuan Christiana, Shi Chenxu, Patchava Shruthi, Halper Elizabeth, Garg Jasmine, Movsesyan Irina, Yin Chaoying, Wu Roland, Wilsbacher Lisa D, Liu Jiandong, Hager Ronald L, Coughlin Shaun R, Jinek Martin, Pullinger Clive R, Kane John P, Hart Daniel O, Kwok Pui-Yan, Deo Rahul C
Аннотация
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.