Zhou, Can, Li, Chen, Zhou, Bin, Sun, Huaqin, Koullourou, Victoria, Holt, Ian, Puckelwartz, Megan J, Warren, Derek T, Hayward, Robert, Lin, Ziyuan, Zhang, Lin, Morris, Glenn E, McNally, Elizabeth M, Shackleton, Sue, Rao, Li, Shanahan, Catherine M and Zhang, Qiuping (2017) Novel nesprin-1 mutations associated with dilated cardiomyopathy cause nuclear envelope disruption and defects in myogenesis. Human Molecular Genetics, 26 (12). pp. 2258-2276. ISSN 0964-6906
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Abstract
Nesprins-1 and -2 are highly expressed in skeletal and cardiac muscle and together with SUN (Sad1p/UNC84)-domain containing proteins and lamin A/C form the LInker of Nucleoskeleton-and-Cytoskeleton (LINC) bridging complex at the nuclear envelope (NE). Mutations in nesprin-1/2 have previously been found in patients with autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD) as well as dilated cardiomyopathy (DCM). In this study, three novel rare variants (R8272Q, S8381C and N8406K) in the C-terminus of the SYNE1 gene (nesprin-1) were identified in seven DCM patients by mutation screening. Expression of these mutants caused nuclear morphology defects and reduced lamin A/C and SUN2 staining at the NE. GST pull-down indicated that nesprin-1/lamin/SUN interactions were disrupted. Nesprin-1 mutations were also associated with augmented activation of the ERK pathway in vitro and in hearts in vivo. During C2C12 muscle cell differentiation, nesprin-1 levels are increased concomitantly with kinesin light chain (KLC-1/2) and immunoprecipitation and GST pull-down showed that these proteins interacted via a recently identified LEWD domain in the C-terminus of nesprin-1. Expression of nesprin-1 mutants in C2C12 cells caused defects in myoblast differentiation and fusion associated with dysregulation of myogenic transcription factors and disruption of the nesprin-1 and KLC-1/2 interaction at the outer nuclear membrane. Expression of nesprin-1α2 WT and mutants in zebrafish embryos caused heart developmental and conduction defects that varied in severity. These findings support a role for nesprin-1 in myogenesis and muscle disease, and uncover a novel mechanism whereby disruption of the LINC complex may contribute to the pathogenesis of DCM.
Item Type: | Article |
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Additional Information: | © The Author 2017. Published by Oxford University Press. |
Faculty \ School: | Faculty of Science > School of Pharmacy (former - to 2024) |
UEA Research Groups: | Faculty of Science > Research Groups > Molecular and Tissue Pharmacology |
Depositing User: | Pure Connector |
Date Deposited: | 27 Apr 2017 05:50 |
Last Modified: | 02 Dec 2024 01:25 |
URI: | https://ueaeprints.uea.ac.uk/id/eprint/63316 |
DOI: | 10.1093/hmg/ddx116 |
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