Mutations in the outer nuclear membrane proteins Nesprin 1 and 2 may be involved in the pathogenesis of Emery-Dreifuss muscular dystrophy (EDMD)-like phenotypes, including cardiomyopathy and dilated cardiomyopathy (DCM). Nesprins belong to a newly discovered family of spectrin-repeat proteins, composed of four members. Nesprin 1 and 2 are believed to anchor nuclei to actin filaments, and are ubiquitously expressed. To investigate functions of Nesprin 1 and 2, we have generated floxed and global knockout mice of both Nesprin 1 and 2. Our studies reveal that Nesprin 2 global knockout mice are viable and have no obvious basal phenotype, whereas over half of Nesprin 1 global knockout (Nesprin 1-/-) mice die perinatally. Remaining Nesprin 1-/- survivors have reduced body weight before three months of age and compromised exercise capacity. Consistent with data from others, we have found 100% perinatal lethality in double knockout mice for Nesprin 1 and 2. Histological analyses of skeletal muscle in Nesprin 1-/- mice and Nesprin 1 and 2 double knockout mice revealed abnormal positioning of non-synaptic nuclei and the disappearance of clusters of synaptic nuclei. We also observed that Nesprin 1-/- mice display abnormal shape and positioning of cardiomyocyte nuclei. In addition, we observed upregulation of protein levels of SUN1, a Nesprin 1 binding partner and an inner nuclear membrane protein, in Nesprin 1-/- heart samples. This 5 year proposal is to investigate the role of Nesprin 1 and 2 in cardiac nuclear position, nuclear membrane structure, and cardiac function by analysis of mutant mice and cells derived from them. Our unique ability to genetically ablate Nesprins in mouse cardiomyocytes, combined with the ability to test molecular and physiological functions in the whole animal, isolated papillary muscles, and cultured cardiomyocytes, will provide novel information as to the function of Nesprins in cardiac structure, function and disease.

Public Health Relevance

Recent data suggest that mutations in Nesprin 1 and 2 may be involved in the pathogenesis of Emery-Dreifuss muscular dystrophy (EDMD)-like phenotypes including cardiomyopathy and dilated cardiomyopathy (DCM). Our proposed studies will help us to understand biological functions of Nesprin 1 and 2 in cardiac structure and function. The proposed studies will also help us gain insight into mechanisms by which mutations in Nesprin 1 are involved in the pathogenesis of DCM, thereby improving our general understanding of DCM.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL106968-04
Application #
8582560
Study Section
Special Emphasis Panel (ZRG1-CVRS-C (02))
Program Officer
Wang, Lan-Hsiang
Project Start
2011-01-01
Project End
2015-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
4
Fiscal Year
2014
Total Cost
$348,750
Indirect Cost
$123,750
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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