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Novel nesprin-1 mutations associated with dilated cardiomyopathy cause nuclear envelope disruption and defects in myogenesis.pdf (1.63 MB)

Novel nesprin-1 mutations associated with dilated cardiomyopathy cause nuclear envelope disruption and defects in myogenesis.

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posted on 2017-06-30, 09:08 authored by Can Zhou, Chen Li, Bin Zhou, Huaqin Sun, Victoria Koullourou, Ian Holt, Megan J. Puckelwartz, Derek T. Warren, Robert Hayward, Ziyuan Lin, Lin Zhang, Glenn E. Morris, Elizabeth M. McNally, Sue Shackleton, Li Rao, Catherine M. Shanahan, Qiuping Zhang
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.

Funding

British Heart Foundation (BHF), UK [PG/11/58/29004 to Q.P.Z., RG/11/14/29056 to C.M.S., PG/11/71/29091 to I.H. and G.E.M.]; National Natural Science Foundation of China [81270289 to L.R.]. Funding to pay Open Access publication charges for this article was provided by the BHF.

History

Citation

Human Molecular Genetics, 2017, 26 (12), pp. 2258-2276

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/MBSP Non-Medical Departments/Molecular & Cell Biology

Version

  • VoR (Version of Record)

Published in

Human Molecular Genetics

Publisher

Oxford University Press (OUP)

issn

0964-6906

eissn

1460-2083

Acceptance date

2017-03-22

Copyright date

2017

Available date

2017-06-30

Publisher version

https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/ddx116

Notes

Supplementary Material is available at HMG online

Language

en

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