Please use this identifier to cite or link to this item: http://hdl.handle.net/2381/39969
Title: Novel nesprin-1 mutations associated with dilated cardiomyopathy cause nuclear envelope disruption and defects in myogenesis.
Authors: 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.
Zhang, Qiuping
First Published: 15-Jun-2017
Publisher: Oxford University Press (OUP)
Citation: Human Molecular Genetics, 2017, 26 (12), pp. 2258-2276
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 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.
DOI Link: 10.1093/hmg/ddx116
ISSN: 0964-6906
eISSN: 1460-2083
Links: https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/ddx116
http://hdl.handle.net/2381/39969
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © the authors, 2017. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Description: Supplementary Material is available at HMG online
Appears in Collections:Published Articles, Dept. of Molecular and Cell Biology

Files in This Item:
File Description SizeFormat 
Novel nesprin-1 mutations associated with dilated cardiomyopathy cause nuclear envelope disruption and defects in myogenesis.pdfPublished (publisher PDF)1.67 MBAdobe PDFView/Open


Items in LRA are protected by copyright, with all rights reserved, unless otherwise indicated.