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Title: Disrupting the LINC complex by AAV mediated gene transduction prevents progression of Lamin induced cardiomyopathy
Authors: Chai, Ruth Jinfen
Werner, Hendrikje
Li, Peter Yiqing 
Lee, Yin Loon
Khaing Thet Nyein
Solovei, Irina
Tuan Danh Anh Luu 
Sharma, Bhavya
Navasankari, Raju
Maric, Martina
Sim, Lois Yu En
Loh, Ying Jie
Aliwarga, Edita 
Cheong, Jason Wen Long
Chojnowski, Alexandre
Autio, Matias Ilmari 
Haiyang, Yu
Boon Tan, Kenneth Kian
Keng, Choong Tat
Ng, Shi Ling 
Chew, Wei Leong
Ferenczi, Michael
Burke, Brian
Foo, Roger Sik Yin 
Stewart, Colin L. 
Issue Date: 5-Aug-2021
Publisher: Nature Research
Citation: Chai, Ruth Jinfen, Werner, Hendrikje, Li, Peter Yiqing, Lee, Yin Loon, Khaing Thet Nyein, Solovei, Irina, Tuan Danh Anh Luu, Sharma, Bhavya, Navasankari, Raju, Maric, Martina, Sim, Lois Yu En, Loh, Ying Jie, Aliwarga, Edita, Cheong, Jason Wen Long, Chojnowski, Alexandre, Autio, Matias Ilmari, Haiyang, Yu, Boon Tan, Kenneth Kian, Keng, Choong Tat, Ng, Shi Ling, Chew, Wei Leong, Ferenczi, Michael, Burke, Brian, Foo, Roger Sik Yin, Stewart, Colin L. (2021-08-05). Disrupting the LINC complex by AAV mediated gene transduction prevents progression of Lamin induced cardiomyopathy. Nature Communications 12 (1) : 4722. ScholarBank@NUS Repository.
Rights: Attribution 4.0 International
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. © 2021, The Author(s).
Source Title: Nature Communications
ISSN: 2041-1723
DOI: 10.1038/s41467-021-24849-4
Rights: Attribution 4.0 International
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