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X-linked Emery-Dreifuss muscular dystrophy (X-EDMD) is inherited through mutations in EMD, which encodes a nuclear membrane protein named emerin. Emerin is expressed in most cells, but EDMD strikes specific tissues. This review summarizes growing evidence that emerin has roles in both tissue-specific gene regulation and the mechanical integrity of the nucleus and discusses how these roles might impact EDMD.
Anat Rec A Discov Mol Cell Evol Biol 2006 Jul
PMID:Multiple roles for emerin: implications for Emery-Dreifuss muscular dystrophy. 1676 Dec 79

Mutations in LMNA, which encodes nuclear lamins A and C, cause a broad range of diseases, including autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD) and related disorders with a predominant cardiomyopathy. Homozygous Lmna model "knock-in" and null mice develop cardiomyopathy, whereas heterozygous mice do not. Overexpression of lamin A mutants that cause cardiomyopathy in cultured cells induces morphological abnormalities in the nuclear envelope and lamina; however, effects on tissue and organ pathology have not been determined. We used the heart-selective alpha-myosin heavy chain promoter to drive expression in transgenic mice of human wild-type and M371K lamin A, which causes EDMD. Mice expressing M371K lamin A were born at approximately 0.07 of the expected frequency and those born typically died at 2-7 weeks of age. Histological analysis showed increased eosinophilia and fragmentation of cardiomyofibrils, nuclear pyknosis and edema without fibrosis or significant inflammation, indicative of acute or subacute injury. Mice expressing human wild-type lamin A were born at only slightly less than the expected frequency and had normal life spans. Confocal immunofluorescence microscopy demonstrated abnormal nuclear envelopes with intranuclear foci of lamins in cardiac cells expressing M371K lamin A. Electron microscopy revealed extensively convoluted nuclear envelopes, intranuclear inclusions and chromatin clumps in cardiomyocyte nuclei. These results demonstrate that expression of a lamin A mutant that induces alterations in nuclear morphology can cause tissue and organ damage in mice with a normal complement of wild-type lamins.
Hum Mol Genet 2006 Aug 15
PMID:Pathology and nuclear abnormalities in hearts of transgenic mice expressing M371K lamin A encoded by an LMNA mutation causing Emery-Dreifuss muscular dystrophy. 1682 83

Emery-Dreifuss muscular dystrophy (EDMD) is a neuromuscular degenerative condition with an associated dilated cardiomyopathy and cardiac conduction defect. It can be inherited in either an X-linked or autosomal manner by mutations in the nuclear proteins emerin and lamin A/C, respectively. Traditionally muscular dystrophies were associated with defects in sarcolemma-associated proteins and, therefore, a nuclear connection suggested the existence of novel signalling pathways associated with this group of diseases. Subsequently, other mutations in the lamin A/C gene were attributed to a range of tissue-specific degenerative conditions, collectively known as the 'laminopathies'. Therefore, any proposed hypothesis underlying the molecular mechanism of EDMD needs to include this anomaly. As we celebrate the 10th anniversary of the identification of emerin as a component of the nuclear envelope, I discuss here the available evidence that currently implicates EDMD as arising from perturbations in myogenic regulatory pathways, causing temporal delays in both cell cycle progression and muscle regeneration.
Cell Mol Life Sci 2006 Dec
PMID:Emery-Dreifuss muscular dystrophy at the nuclear envelope: 10 years on. 1701 57

X-linked Emery-Dreifuss muscular dystrophy (X-EDMD) is inherited through mutations in emerin, a nuclear membrane protein. Emerin has proposed roles in nuclear architecture and gene regulation, but direct molecular links to disease were unknown. We report that Lim-domain only 7 (Lmo7) binds emerin directly with 125 nM affinity; the C-terminal half of human Lmo7 (hLmo7C) was sufficient to bind emerin in vitro. Lmo7 appeared relevant to EDMD because a deletion that removes Lmo7 (plus eight exons of a neighboring gene) in mice causes dystrophic muscles [Semenova, E., Wang, X., Jablonski, M.M., Levorse, J. and Tilghman, S.M. (2003) An engineered 800 kilobase deletion of Uchl3 and Lmo7 on mouse chromosome 14 causes defects in viability, postnatal growth and degeneration of muscle and retina. Hum. Mol. Genet., 12, 1301-1312]. Lmo7 localizes in the nucleus, cytoplasm and cell surface, particularly adhesion junctions [Ooshio, T., Irie, K., Morimoto, K., Fukuhara, A., Imai, T. and Takai, Y. (2004) Involvement of LMO7 in the association of two cell-cell adhesion molecules, nectin and E-cadherin, through afadin and alpha-actinin in epithelial cells. J. Biol. Chem., 279, 31365-31373]. Our data suggest endogenous Lmo7 is a nucleocytoplasmic shuttling protein, and might also localize at focal adhesions in HeLa cells. Two key results show that Lmo7 regulates emerin gene expression: rat Lmo7 isoforms directly activated a luciferase reporter gene in vivo, and emerin mRNA expression decreased 93% in Lmo7-downregulated HeLa cells. Thus, Lmo7 not only binds emerin protein but is also required for emerin gene transcription. Microarray analysis of Lmo7-downregulated HeLa cells identified over 4200 misregulated genes, including 46 genes important for muscle or heart. Misregulation of 11 genes, including four (CREBBP, NAP1L1, LAP2, RBL2) known to be misregulated in X-EDMD patients and emerin-null mice [Bakay, M., Wang, Z., Melcon, G., Schiltz, L., Xuan, J., Zhao, P., Sartorelli, V., Seo, J., Pegoraro, E., Angelini, C. et al. (2006) Nuclear envelope dystrophies show a transcriptional fingerprint suggesting disruption of Rb-MyoD pathways in muscle regeneration. Brain, 129, 996-1013; Melcon, G., Kozlov, S., Cutler, D.A., Sullivan, T., Hernandez, L., Zhao, P., Mitchell, S., Nader, G., Bakay, M., Rottman, J.N. et al. (2006) Loss of emerin at the nuclear envelope disrupts the Rb1/E2F and MyoD pathways during muscle regeneration. Hum. Mol. Genet., 15, 637-651] was confirmed by real-time PCR. Overexpression of wild-type emerin, but not emerin mutant P183H (which causes EDMD and selectively disrupts binding to Lmo7), decreased the expression of CREBBP, NAP1L1 and LAP2, suggesting Lmo7 activity is both EDMD-relevant and inhibited by direct binding to emerin. We conclude that Lmo7 positively regulates many EDMD-relevant genes (including emerin), and is feedback-regulated by binding to emerin.
Hum Mol Genet 2006 Dec 01
PMID:Lmo7 is an emerin-binding protein that regulates the transcription of emerin and many other muscle-relevant genes. 1706 98

Emery-Dreifuss muscular dystrophy (EDMD) is an inherited disorder characterized by slowly progressive skeletal muscle weakness in a humero-peroneal distribution, early contractures and prominent cardiomyopathy with conduction block. Mutations in EMD, encoding emerin, and LMNA, encoding A-type lamins, respectively, cause X-linked and autosomal dominant EDMD. Emerin and A-type lamins are proteins of the inner membrane of the nuclear envelope. Whereas the genetic cause of EDMD has been described and the proteins well characterized, little is known on how abnormalities in nuclear envelope proteins cause striated muscle disease. In this study, we analyzed genome-wide expression profiles in hearts from Emd knockout mice, a model of X-linked EDMD, using Affymetrix GeneChips. This analysis showed a molecular signature similar to that we previously described in hearts from Lmna H222P knock-in mice, a model of autosomal dominant EDMD. There was a common activation of the ERK1/2 branch of the mitogen-activated protein kinase (MAPK) pathway in both murine models, as well as activation of downstream targets implicated in the pathogenesis of cardiomyopathy. Activation of MAPK signaling appears to be a cornerstone in the development of heart disease in both X-linked and autosomal dominant EDMD.
Hum Mol Genet 2007 Aug 01
PMID:Activation of MAPK in hearts of EMD null mice: similarities between mouse models of X-linked and autosomal dominant Emery Dreifuss muscular dystrophy. 1756 79

Emery-Dreifuss muscular dystrophy (EDMD) is a heterogeneous late-onset disease involving skeletal muscle wasting and heart defects caused, in a minority of cases, by mutations in either of two genes encoding the inner nuclear membrane (INM) proteins, emerin and lamins A/C. Nesprin-1 and -2 are multi-isomeric, spectrin-repeat proteins that bind both emerin and lamins A/C and form a network in muscle linking the nucleoskeleton to the INM, the outer nuclear membrane, membraneous organelles, the sarcomere and the actin cytoskeleton. Thus, disruptions in nesprin/lamin/emerin interactions might play a role in the muscle-specific pathogenesis of EDMD. Screening for DNA variations in the genes encoding nesprin-1 (SYNE1) and nesprin-2 (SYNE2) in 190 probands with EDMD or EDMD-like phenotypes identified four heterozygous missense mutations. Fibroblasts from these patients exhibited nuclear morphology defects and specific patterns of emerin and SUN2 mislocalization. In addition, diminished nuclear envelope localization of nesprins and impaired nesprin/emerin/lamin binding interactions were common features of all EDMD patient fibroblasts. siRNA knockdown of nesprin-1 or -2 in normal fibroblasts reproduced the nuclear morphological changes and mislocalization of emerin and SUN2 observed in patient fibroblasts. Taken together, these data suggest that EDMD may be caused, in part, by uncoupling of the nucleoskeleton and cytoskeleton because of perturbed nesprin/emerin/lamin interactions.
Hum Mol Genet 2007 Dec 01
PMID:Nesprin-1 and -2 are involved in the pathogenesis of Emery Dreifuss muscular dystrophy and are critical for nuclear envelope integrity. 1776 84

Autosomal Emery-Dreifuss muscular dystrophy and related disorders with dilated cardiomyopathy and variable skeletal muscle involvement are caused by mutations in LMNA, which encodes A-type nuclear lamins. How alterations in A-type lamins, intermediate filament proteins of the nuclear envelope expressed in most differentiated somatic cells, cause cardiomyopathy is only poorly understood. We demonstrated previously abnormal activation of the extracellular signal-regulated kinase (ERK) branch of the mitogen-activated protein kinase (MAPK) signaling cascade in hearts of Lmna H222P 'knock in' mice, a model of autosomal Emery-Dreifuss muscular dystrophy. We therefore treated Lmna(H222P/H222P) mice that develop cardiomyopathy with PD98059, an inhibitor of ERK activation. Systemic treatment of Lmna(H222P/H222P) mice with PD98059 inhibited ERK phosphorylation and blocked the activation of downstream genes in heart. It also blocked increased expression of RNAs encoding natriuretic peptide precursors and proteins involved in sarcomere organization that occurred in placebo-treated mice. Histological analysis and echocardiography demonstrated that treatment with PD98059 delayed the development of left ventricular dilatation. PD98059-treated Lmna(H222P/H222P) mice had normal cardiac ejection fractions assessed by echocardiography when placebo-treated mice had a 30% decrease. These results emphasize the role of ERK activation in the development of cardiomyopathy caused by LMNA mutations. They further provide proof of principle for ERK inhibition as a therapeutic option to prevent or delay heart failure in humans with Emery-Dreifuss muscular dystrophy and related disorders caused by mutations in LMNA.
Hum Mol Genet 2009 Jan 15
PMID:Inhibition of extracellular signal-regulated kinase signaling to prevent cardiomyopathy caused by mutation in the gene encoding A-type lamins. 1892 24

The mechanical properties of the interphase nucleus have important implications for cellular function and can reflect changes in nuclear envelope structure and/or chromatin organization. Mutations in the nuclear envelope proteins lamin A and C cause several human diseases, such as Emery-Dreifuss muscular dystrophy, and dramatic changes in nuclear stiffness have been reported in cells from lamin A/C-deficient mice. We have developed a cellular strain technique to measure nuclear stiffness in intact, adherent cells and have applied this experimental method to fibroblasts from mouse models of Emery-Dreifuss muscular dystrophy and to skin fibroblasts from laminopathy patients and healthy control subjects. The experimental protocol is based on measuring induced nuclear deformations in cells plated on a flexible silicone substrate; the nuclear stiffness can subsequently be inferred from the ratio of induced nuclear strain to the applied membrane strain. These experiments reveal that lamins A and C are important determinants of nuclear stiffness and that lamin mutations associated with muscular dystrophies and other laminopathies often result in disturbed nuclear stiffness that could contribute to the tissue-specific disease phenotypes.
Methods Mol Biol 2009
PMID:Mechanical properties of interphase nuclei probed by cellular strain application. 1895 Nov 77

Mutations in certain nuclear envelope (NE) proteins cause muscular dystrophies and other disorders, but the disease mechanisms remain unclear. The nuclear envelope transmembrane protein NET25 (Lem2) is a truncated paralog of MAN1, an NE component linked to bone disorders. NET25 and MAN1 share an approximately 40-residue LEM homology domain with emerin, the protein mutated in X-linked Emery-Dreifuss muscular dystrophy. However, roles for NET25 and MAN1 in myogenesis have not yet been described. Using RNA interference in C2C12 myoblasts, we show for the first time that both NET25 and MAN1 are required for myogenic differentiation. NET25 depletion causes hyperactivation of extracellular signal-regulated kinase 1/2 at the onset of differentiation, and pharmacological inhibition of this transient overactivation rescues myogenesis. In contrast, pharmacological inhibition of both mitogen-activated protein kinase and transforming growth factor beta signaling is required to rescue differentiation after MAN1 depletion. Ectopic expression of silencing-resistant NET25 rescues myogenesis after depletion of emerin but not after MAN1 silencing. Thus, NET25 and emerin have at least partially overlapping functions during myogenic differentiation, which are distinct from those of MAN1. Our work supports the hypothesis that deregulation of cell signaling contributes to NE-linked disorders and suggests that mutations in NET25 and MAN1 may cause muscle diseases.
Mol Cell Biol 2009 Nov
PMID:Overlapping functions of nuclear envelope proteins NET25 (Lem2) and emerin in regulation of extracellular signal-regulated kinase signaling in myoblast differentiation. 1972 Jul 41

Nesprin 1 is an outer nuclear membrane protein that is thought to link the nucleus to the actin cytoskeleton. Recent data suggest that mutations in Nesprin 1 may also be involved in the pathogenesis of Emery-Dreifuss muscular dystrophy. To investigate the function of Nesprin 1 in vivo, we generated a mouse model in which all isoforms of Nesprin 1 containing the C-terminal spectrin-repeat region with or without KASH domain were ablated. Nesprin 1 knockout mice are marked by decreased survival rates, growth retardation and increased variability in body weight. Additionally, nuclear positioning and anchorage are dysfunctional in skeletal muscle from knockout mice. Physiological testing demonstrated no significant reduction in stress production in Nesprin 1-deficient skeletal muscle in either neonatal or adult mice, but a significantly lower exercise capacity in knockout mice. Nuclear deformation testing revealed ineffective strain transmission to nuclei in muscle fibers lacking Nesprin 1. Overall, our data show that Nesprin 1 is essential for normal positioning and anchorage of nuclei in skeletal muscle.
Hum Mol Genet 2010 Jan 15
PMID:Nesprin 1 is critical for nuclear positioning and anchorage. 1986 91


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