PUBLICATION
Novel nesprin-1 mutations associated with dilated cardiomyopathy cause nuclear envelope disruption and defects in myogenesis
- Authors
- Zhou, C., Li, C., Zhou, B., Sun, H., Koullourou, V., Holt, I., Puckelwartz, M.J., Warren, D.T., Hayward, R., Lin, Z., Zhang, L., Morris, G.E., McNally, E.M., Shackleton, S., Rao, L., Shanahan, C.M., Zhang, Q.
- ID
- ZDB-PUB-170412-4
- Date
- 2017
- Source
- Human molecular genetics 26(12): 2258-2276 (Journal)
- Registered Authors
- Keywords
- cardiomyopathy, dilated, immunoprecipitation, mutation, myogenesis, cytoskeleton, embryo, genes, nuclear envelope, zebrafish, heart, transcription factor, lamins, muscle cells, lamin type a, myoblasts
- MeSH Terms
-
- Animals
- Cardiomyopathy, Dilated/genetics
- Cardiomyopathy, Dilated/metabolism
- Cell Culture Techniques
- Cytoskeleton/metabolism
- Humans
- Lamin Type A/genetics
- Membrane Proteins/genetics
- Microfilament Proteins/genetics
- Microtubule-Associated Proteins/genetics
- Microtubule-Associated Proteins/metabolism
- Muscle Development/genetics
- Muscle Development/physiology
- Muscular Dystrophy, Emery-Dreifuss/genetics
- Mutation
- Nerve Tissue Proteins/genetics*
- Nerve Tissue Proteins/metabolism*
- Nuclear Envelope/metabolism
- Nuclear Proteins/genetics*
- Nuclear Proteins/metabolism*
- Zebrafish/genetics
- PubMed
- 28398466 Full text @ Hum. Mol. Genet.
Citation
Zhou, C., Li, C., Zhou, B., Sun, H., Koullourou, V., Holt, I., Puckelwartz, M.J., Warren, D.T., Hayward, R., Lin, Z., Zhang, L., Morris, G.E., McNally, E.M., Shackleton, S., Rao, L., Shanahan, C.M., Zhang, Q. (2017) Novel nesprin-1 mutations associated with dilated cardiomyopathy cause nuclear envelope disruption and defects in myogenesis. Human molecular genetics. 26(12):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 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping