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

Ruth Jinfen Chai,Shi Ling Ng,Yin Loon Lee,Ying Jie Loh,Colin L Stewart,Tuan Danh Anh Luu,Jason Wen Long Cheong,Peter Yiqing Li,Hendrikje Werner,Brian Burke,Khaing Thet Nyein,Martina Maric,Matias Autio ,Irina Solovei,Edita Aliwarga,Michael A Ferenczi ,Lois Yu En Sim,Raju Navasankari,Roger Foo ,Choong Tat Keng,B.s Sharma ,Hongwei Yu ,Kenneth K B Tan ,Wei Leong Chew,Alexandre Chojnowski

doi:10.1038/s41467-021-24849-4

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.

Highlights

Mutations in the LaminA gene are a common cause of monogenic dilated cardiomyopathy
We demonstrate that disruption of the LINC complex in individuals carrying Lamin A (LMNA) mutations, Associated Virus (AAV) mediated delivery of a DN-SUN1 to CMs may be of therapeutic benefit to patients with LMNA associated Dilated Cardiomyopathy (DCM)
Performing the same Lmna deletion on a Sun[2] null background did not extend the longevity of LmnaΔ/Δ mice, revealing the longevity extension is specific to the loss of Sun[1] even though SUN2 is expressed in multiple tissues, including cardiomyocytes (Supplementary Fig. 1)

Summary

Introduction

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. Dilated Cardiomyopathy (DCM) is the most common disease affecting heart muscle, accounting for ~60% of all cardiomyopathies It is characterized by reduced systolic (contractile) function due to enlargement and thinning of the left ventricular wall. The lamins interact with numerous INM proteins, including Emerin, the Lamina-Associated Polypeptides (LAPs), and the SUN domain proteins[15], many of which are either mutated or present as a variant linked to heart disease[16,17]. Together these proteins comprise an integrated protein network, centered on the lamina, where loss or mutation of the lamins can result in either the mislocalization or a change in their expression levels (emerin, SUN1, LBR, LAP1c, and Lap[2] isoforms)[8,14,18,19,20]

Methods

Results

Conclusion