Disrupting the LINC complex by AAV mediated gene transduction prevents progression of Lamin induced cardiomyopathy

Ruth Jinfen Chai, Hendrikje Werner, Peter Yiqing Li, Yin Loon Lee, Khaing Thet Nyein, Irina Solovei, Tuan Danh Anh Luu, Bhavya Sharma, Raju Navasankari, Martina Maric, Lois Yu En Sim, Ying Jie Loh, Edita Aliwarga, Jason Wen Long Cheong, Alexandre Chojnowski, Matias Ilmari Autio, Yu Haiyang, Kenneth Kian Boon Tan, Choong Tat Keng, Shi Ling Ng, Wei Leong Chew, Michael Ferenczi, Brian Burke, Roger Sik Yin Foo () and Colin L. Stewart ()
Additional contact information
Ruth Jinfen Chai: Agency for Science, Technology and Research (A*STAR)
Hendrikje Werner: Agency for Science, Technology and Research (A*STAR)
Peter Yiqing Li: National University of Singapore
Yin Loon Lee: Agency for Science, Technology and Research (A*STAR)
Khaing Thet Nyein: Agency for Science, Technology and Research (A*STAR)
Irina Solovei: Ludwig Maximilians University Munich
Tuan Danh Anh Luu: National University of Singapore
Bhavya Sharma: Agency for Science, Technology and Research (A*STAR)
Raju Navasankari: Agency for Science, Technology and Research (A*STAR)
Martina Maric: Agency for Science, Technology and Research (A*STAR)
Lois Yu En Sim: Agency for Science, Technology and Research (A*STAR)
Ying Jie Loh: Agency for Science, Technology and Research (A*STAR)
Edita Aliwarga: National University of Singapore
Jason Wen Long Cheong: Agency for Science, Technology and Research (A*STAR)
Alexandre Chojnowski: Agency for Science, Technology and Research (A*STAR)
Matias Ilmari Autio: Agency for Science, Technology and Research (A*STAR)
Yu Haiyang: Nanyang Technological University
Kenneth Kian Boon Tan: Agency for Science, Technology and Research (A*STAR)
Choong Tat Keng: Agency for Science, Technology and Research (A*STAR)
Shi Ling Ng: National University of Singapore
Wei Leong Chew: Agency for Science, Technology and Research (A*STAR)
Michael Ferenczi: Nanyang Technological University
Brian Burke: Agency for Science, Technology and Research (A*STAR)
Roger Sik Yin Foo: National University of Singapore
Colin L. Stewart: Agency for Science, Technology and Research (A*STAR)

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract Mutations in the LaminA gene are a common cause of monogenic dilated cardiomyopathy. Here we show that mice with a cardiomyocyte-specific Lmna deletion develop cardiac failure and die within 3–4 weeks after inducing the mutation. When the same Lmna mutations are induced in mice genetically deficient in the LINC complex protein SUN1, life is extended to more than one year. Disruption of SUN1’s function is also accomplished by transducing and expressing a dominant-negative SUN1 miniprotein in Lmna deficient cardiomyocytes, using the cardiotrophic Adeno Associated Viral Vector 9. The SUN1 miniprotein disrupts binding between the endogenous LINC complex SUN and KASH domains, displacing the cardiomyocyte KASH complexes from the nuclear periphery, resulting in at least a fivefold extension in lifespan. Cardiomyocyte-specific expression of the SUN1 miniprotein prevents cardiomyopathy progression, potentially avoiding the necessity of developing a specific therapeutic tailored to treating each different LMNA cardiomyopathy-inducing mutation of which there are more than 450.

Date: 2021
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DOI: 10.1038/s41467-021-24849-4

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