Nesprin-1 and actin contribute to nuclear and cytoskeletal defects in lamin A/C-deficient cardiomyopathy

Nikolova-Krstevski, Vesna; Leimena, Christiana; Xiao, Xiao-Hui; Kesteven, Scott; Tan, Ju Chiat; Yeo, Li Sze; Yu, Ze‐Yan; Zhang, Qiuping; Carlton, Arthur; Head, Stewart I.; Shanahan, Catherine M.; Feneley, Michael P.; Fatkin, Diane

doi:10.1016/j.yjmcc.2010.12.001

Cited by 30 publications

(20 citation statements)

References 30 publications

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“…26 The NE-anchored nesprin-1 protein responds to mechanical force initiated at the cell surface through its interaction with cytoplasmic actin, and thereby affects downstream molecular changes in the nucleus. 39 Studies in mice demonstrate that nesprin-1 coordinates the proper biomechanical gene response in cardiomyocytes and contributes to the cytoskeletal defects in LMNA -deficient cardiomyopathy; heterozygous nesprin mice display cardiac defects (M. Pucklewartz, personal communication 40 ), and SYNE1 variants have been identified in at least two families with DCM, with or without skeletal muscle involvement. 24,47 Physical disruption of normal LINC complex interactions is therefore a plausible biological mechanism underlying the cardiomyopathy in our patient and father.…”

Section: Discussionmentioning

confidence: 99%

Whole Exome Sequencing Identifies Truncating Variants in Nuclear Envelope Genes in Patients With Cardiovascular Disease

Haskell

Jensen²,

Samsa³

et al. 2017

Circ Cardiovasc Genet

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Background The genetic variation underlying many heritable forms of cardiovascular disease is incompletely understood, even in patients with strong family history or early age at onset. Methods and Results We used whole exome sequencing to detect pathogenic variants in 55 patients with suspected monogenic forms of cardiovascular disease. Diagnostic analysis of established disease genes identified pathogenic variants in 21.8% of cases, and variants of uncertain significance in 34.5% of cases. Three patients harbored heterozygous nonsense or splice-site variants in the nucleoporin genes NUP37, NUP43, and NUP188, which have not been implicated previously in cardiac disease. We also identified a heterozygous splice site variant in the nuclear envelope gene SYNE1 in a child with severe dilated cardiomyopathy that underwent transplant, as well as in his affected father. To confirm a cardiovascular role for these candidate genes in vivo, we used morpholinos to reduce SYNE1, NUP37, and NUP43 gene expression in zebrafish. Morphant embryos displayed cardiac abnormalities, including pericardial edema and heart failure. Furthermore, lymphoblasts from the patient carrying a SYNE1 splice-site variant displayed changes in nuclear morphology and protein localization that are consistent with disruption of the nuclear envelope. Conclusions These data expand the repertoire of pathogenic variants associated with cardiovascular disease, and validate the diagnostic and research utility of whole exome sequencing. We identify NUP37, NUP43, and NUP188 as novel candidate genes for cardiovascular disease, and suggest that dysfunction of the nuclear envelope may be an under-recognized component of inherited cardiac disease in some cases.

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Section: Discussionmentioning

confidence: 99%

Whole Exome Sequencing Identifies Truncating Variants in Nuclear Envelope Genes in Patients With Cardiovascular Disease

Haskell

Jensen²,

Samsa³

et al. 2017

Circ Cardiovasc Genet

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“…Multiple nesprin mutations have been identified in Emery Dreifuss Muscular Dystrophy (EDMD), Dilated Cardiomyopathies (DCM), autosomal recessive arthrogryposis (ARA) and autosomal recessive cerebellar ataxia (ARCA1) [15], [17], [18], [50], [51]. The nesprin mutations promoting EDMD and DCM presumably affect LINC nesprin variants resulting in abnormal nuclear morphology and function.…”

Section: Discussionmentioning

confidence: 99%

Multiple Novel Nesprin-1 and Nesprin-2 Variants Act as Versatile Tissue-Specific Intracellular Scaffolds

et al. 2012

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BackgroundNesprins (Nuclear envelope spectrin-repeat proteins) are a novel family of giant spectrin-repeat containing proteins. The nesprin-1 and nesprin-2 genes consist of 146 and 116 exons which encode proteins of ∼1mDa and ∼800 kDa is size respectively when all the exons are utilised in translation. However emerging data suggests that the nesprins have multiple alternative start and termination sites throughout their genes allowing the generation of smaller isoforms.ResultsIn this study we set out to identify novel alternatively transcribed nesprin variants by screening the EST database and by using RACE analysis to identify cDNA ends. These two methods provided potential hits for alternative start and termination sites that were validated by PCR and DNA sequencing. We show that these alternative sites are not only expressed in a tissue specific manner but by combining different sites together it is possible to create a wide array of nesprin variants. By cloning and expressing small novel nesprin variants into human fibroblasts and U2OS cells we show localization to actin stress-fibres, focal adhesions, microtubules, the nucleolus, nuclear matrix and the nuclear envelope (NE). Furthermore we show that the sub-cellular localization of individual nesprin variants can vary depending on the cell type, suggesting any single nesprin variant may have different functions in different cell types.ConclusionsThese studies suggest nesprins act as highly versatile tissue specific intracellular protein scaffolds and identify potential novel functions for nesprins beyond cytoplasmic-nuclear coupling. These alternate functions may also account for the diverse range of disease phenotypes observed when these genes are mutated.

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“…Recent reviews of cardiac disease have identified classes of genes, with those of the actin cytoskeleton being most prominent among them, whose dysfunction leads to dilated cardiomyopathy (Sheikh et al, 2006; Gustafson-Wagner et al, 2007; Purevjav et al, 2010; Nikolova-Krstevski et al, 2011). Although it is clear that the MT network impacts both development and function of the heart, direct linkage of any MT-network-associated gene product to cardiac disease had not yet been established (Dellefave and McNally, 2010).…”

Section: Discussionmentioning

confidence: 99%

Cardiac-specific deletion of the microtubule-binding protein CENP-F causes dilated cardiomyopathy

Dees

Miller

Moynihan

et al. 2012

Disease Models &Amp; Mechanisms

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SUMMARYCENP-F is a large multifunctional protein with demonstrated regulatory roles in cell proliferation, vesicular transport and cell shape through its association with the microtubule (MT) network. Until now, analysis of CENP-F has been limited to in vitro analysis. Here, using a Cre-loxP system, we report the in vivo disruption of CENP-F gene function in murine cardiomyocytes, a cell type displaying high levels of CENP-F expression. Loss of CENP-F function in developing myocytes leads to decreased cell division, blunting of trabeculation and an initially smaller, thin-walled heart. Still, embryos are born at predicted mendelian ratios on an outbred background. After birth, hearts lacking CENP-F display disruption of their intercalated discs and loss of MT integrity particularly at the costamere; these two structures are essential for cell coupling/electrical conduction and force transduction in the heart. Inhibition of myocyte proliferation and cell coupling as well as loss of MT maintenance is consistent with previous reports of generalized CENP-F function in isolated cells. One hundred percent of these animals develop progressive dilated cardiomyopathy with heart block and scarring, and there is a 20% mortality rate. Importantly, although it has long been postulated that the MT cytoskeleton plays a role in the development of heart disease, this study is the first to reveal a direct genetic link between disruption of this network and cardiomyopathy. Finally, this study has broad implications for development and disease because CENP-F loss of function affects a diverse array of cell-type-specific activities in other organs.

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Nesprin-1 and actin contribute to nuclear and cytoskeletal defects in lamin A/C-deficient cardiomyopathy

Cited by 30 publications

References 30 publications

Whole Exome Sequencing Identifies Truncating Variants in Nuclear Envelope Genes in Patients With Cardiovascular Disease

Whole Exome Sequencing Identifies Truncating Variants in Nuclear Envelope Genes in Patients With Cardiovascular Disease

Multiple Novel Nesprin-1 and Nesprin-2 Variants Act as Versatile Tissue-Specific Intracellular Scaffolds

Cardiac-specific deletion of the microtubule-binding protein CENP-F causes dilated cardiomyopathy

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