An internal promoter underlies the difference in disease severity between N- and C-terminal truncation mutations of Titin in zebrafish
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 diseas...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2015-10-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/09406 |
| _version_ | 1811253371966849024 |
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| author | 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 Jinek Clive R Pullinger John P Kane Daniel O Hart Pui-Yan Kwok Rahul C Deo |
| author_facet | 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 Jinek Clive R Pullinger John P Kane Daniel O Hart Pui-Yan Kwok Rahul C Deo |
| author_sort | Jun Zou |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T16:49:55Z |
| format | Article |
| id | doaj.art-64ef752df04c4b96ab2dff639a70afb6 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T16:49:55Z |
| publishDate | 2015-10-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-64ef752df04c4b96ab2dff639a70afb62022-12-22T03:24:25ZengeLife Sciences Publications LtdeLife2050-084X2015-10-01410.7554/eLife.09406An internal promoter underlies the difference in disease severity between N- and C-terminal truncation mutations of Titin in zebrafishJun Zou0Diana Tran1Mai Baalbaki2Ling Fung Tang3Annie Poon4Angelo Pelonero5Erron W Titus6https://orcid.org/0000-0001-6868-9121Christiana Yuan7Chenxu Shi8Shruthi Patchava9Elizabeth Halper10Jasmine Garg11Irina Movsesyan12Chaoying Yin13Roland Wu14Lisa D Wilsbacher15Jiandong Liu16Ronald L Hager17https://orcid.org/0000-0002-5128-4635Shaun R Coughlin18Martin Jinek19Clive R Pullinger20John P Kane21Daniel O Hart22Pui-Yan Kwok23Rahul C Deo24Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United StatesCardiovascular Research Institute, University of California, San Francisco, San Francisco, United StatesCardiovascular Research Institute, University of California, San Francisco, San Francisco, United StatesCardiovascular Research Institute, University of California, San Francisco, San Francisco, United StatesCardiovascular Research Institute, University of California, San Francisco, San Francisco, United StatesCardiovascular Research Institute, University of California, San Francisco, San Francisco, United StatesCardiovascular Research Institute, University of California, San Francisco, San Francisco, United StatesCardiovascular Research Institute, University of California, San Francisco, San Francisco, United StatesCardiovascular Research Institute, University of California, San Francisco, San Francisco, United StatesCardiovascular Research Institute, University of California, San Francisco, San Francisco, United StatesCardiovascular Research Institute, University of California, San Francisco, San Francisco, United StatesCardiovascular Research Institute, University of California, San Francisco, San Francisco, United StatesCardiovascular Research Institute, University of California, San Francisco, San Francisco, United StatesDepartment of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, United States; McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, United StatesCardiovascular Research Institute, University of California, San Francisco, San Francisco, United States; Department of Medicine, University of California, San Francisco, San Francisco, United StatesCardiovascular Research Institute, University of California, San Francisco, San Francisco, United States; Department of Medicine, University of California, San Francisco, San Francisco, United StatesDepartment of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, United States; McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, United StatesDepartment of Exercise Sciences, Brigham Young University, Provo, United StatesCardiovascular Research Institute, University of California, San Francisco, San Francisco, United States; Department of Medicine, University of California, San Francisco, San Francisco, United StatesDepartment of Biochemistry, University of Zurich, Zurich, SwitzerlandCardiovascular Research Institute, University of California, San Francisco, San Francisco, United States; Department of Physiological Nursing, University of California, San Francisco, San Francisco, United StatesCardiovascular Research Institute, University of California, San Francisco, San Francisco, United States; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United StatesCardiovascular Research Institute, University of California, San Francisco, San Francisco, United States; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United StatesCardiovascular Research Institute, University of California, San Francisco, San Francisco, United States; Department of Dermatology, University of California, San Francisco, San Francisco, United States; Institute for Human Genetics, University of California, San Francisco, United StatesCardiovascular Research Institute, University of California, San Francisco, San Francisco, United States; Department of Medicine, University of California, San Francisco, San Francisco, United States; Institute for Human Genetics, University of California, San Francisco, United States; California Institute for Quantitative Biosciences, San Francisco, United StatesTruncating 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.https://elifesciences.org/articles/09406geneticcardiomyopathysarcomere |
| spellingShingle | 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 Jinek Clive R Pullinger John P Kane Daniel O Hart Pui-Yan Kwok Rahul C Deo An internal promoter underlies the difference in disease severity between N- and C-terminal truncation mutations of Titin in zebrafish eLife genetic cardiomyopathy sarcomere |
| title | An internal promoter underlies the difference in disease severity between N- and C-terminal truncation mutations of Titin in zebrafish |
| title_full | An internal promoter underlies the difference in disease severity between N- and C-terminal truncation mutations of Titin in zebrafish |
| title_fullStr | An internal promoter underlies the difference in disease severity between N- and C-terminal truncation mutations of Titin in zebrafish |
| title_full_unstemmed | An internal promoter underlies the difference in disease severity between N- and C-terminal truncation mutations of Titin in zebrafish |
| title_short | An internal promoter underlies the difference in disease severity between N- and C-terminal truncation mutations of Titin in zebrafish |
| title_sort | internal promoter underlies the difference in disease severity between n and c terminal truncation mutations of titin in zebrafish |
| topic | genetic cardiomyopathy sarcomere |
| url | https://elifesciences.org/articles/09406 |
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