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1.
Brown CA Lanning RW McKinney KQ Salvino AR Cherniske E Crowe CA Darras BT Gominak S Greenberg CR Grosmann C Heydemann P Mendell JR Pober BR Sasaki T Shapiro F Simpson DA Suchowersky O Spence JE 《American journal of medical genetics》2001,102(4):359-367
Emery-Dreifuss muscular dystrophy (EDMD) is characterized by slowly progressive muscle wasting and weakness; early contractures of the elbows, Achilles tendons, and spine; and cardiomyopathy associated with cardiac conduction defects. Clinically indistinguishable X-linked and autosomal forms of EDMD have been described. Mutations in the STA gene, encoding the nuclear envelope protein emerin, are responsible for X-linked EDMD, while mutations in the LMNA gene encoding lamins A and C by alternative splicing have been found in patients with autosomal dominant, autosomal recessive, and sporadic forms of EDMD. We report mutations in LMNA found in four familial and seven sporadic cases of EDMD, including seven novel mutations. Nine missense mutations and two small in-frame deletions were detected distributed throughout the gene. Most mutations (7/11) were detected within the LMNA exons encoding the central rod domain common to both lamins A/C. All of these missense mutations alter residues in the lamin A/C proteins conserved throughout evolution, implying an essential structural and/or functional role of these residues. One severely affected patient possesed two mutations, one specific to lamin A that may modify the phenotype of this patient. Mutations in LMNA were frequently identified among patients with sporadic and familial forms of EDMD. Further studies are needed to identify the factors modifying disease phenotype among patients harboring mutations within lamin A/C and to determine the effect of various mutations on lamin A/C structure and function. 相似文献
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Lamin A/C and emerin are critical for skeletal muscle satellite cell differentiation 总被引:10,自引:0,他引:10 下载免费PDF全文
Frock RL Kudlow BA Evans AM Jameson SA Hauschka SD Kennedy BK 《Genes & development》2006,20(4):486-500
Mutations within LMNA, encoding A-type nuclear lamins, are associated with multiple tissue-specific diseases, including Emery-Dreifuss (EDMD2/3) and Limb-Girdle muscular dystrophy (LGMD1B). X-linked EDMD results from mutations in emerin, a lamin A-associated protein. The mechanisms through which these mutations cause muscular dystrophy are not understood. Here we show that most, but not all, cultured muscle cells from lamin A/C knockout mice exhibit impaired differentiation kinetics and reduced differentiation potential. Similarly, normal muscle cells that have been RNA interference (RNAi) down-regulated for either A-type lamins or emerin have impaired differentiation potentials. Replicative myoblasts lacking A-type lamins or emerin also have decreased levels of proteins important for muscle differentiation including pRB, MyoD, desmin, and M-cadherin; up-regulated Myf5; but no changes in Pax3, Pax7, MEF2C, MEF2D, c-met, and beta-catenin. To determine whether impaired myogenesis is linked to reduced MyoD or desmin levels, these proteins were individually expressed in Lmna(-/-) myoblasts that were then induced to undergo myogenesis. Expression of either MyoD or, more surprisingly, desmin in Lmna(-/-) myoblasts resulted in increased differentiation potential. These studies indicate roles for A-type lamins and emerin in myogenic differentiation and also suggest that these effects are at least in part due to decreased endogenous levels of other critical myoblast proteins. The delayed differentiation kinetics and decreased differentiation potential of lamin A/C-deficient and emerin-deficient myoblasts may in part underlie the dystrophic phenotypes observed in patients with EDMD. 相似文献
3.
Robert W. Lanning Kimberly Q. McKinney Ann R. Salvino Elizabeth Cherniske Carol A. Crowe Basil T. Darras Stasha Gominak Cheryl R. Greenberg Carla Grosmann Peter Heydemann Jerry R. Mendell Barbara R. Pober Takeshi Sasaki Frederick Shapiro David A. Simpson Oksana Suchowersky J. Edward Spence 《American journal of medical genetics. Part A》2001,102(4):359-367
Emery‐Dreifuss muscular dystrophy (EDMD) is characterized by slowly progressive muscle wasting and weakness; early contractures of the elbows, Achilles tendons, and spine; and cardiomyopathy associated with cardiac conduction defects. Clinically indistinguishable X‐linked and autosomal forms of EDMD have been described. Mutations in the STA gene, encoding the nuclear envelope protein emerin, are responsible for X‐linked EDMD, while mutations in the LMNA gene encoding lamins A and C by alternative splicing have been found in patients with autosomal dominant, autosomal recessive, and sporadic forms of EDMD. We report mutations in LMNA found in four familial and seven sporadic cases of EDMD, including seven novel mutations. Nine missense mutations and two small in‐frame deletions were detected distributed throughout the gene. Most mutations (7/11) were detected within the LMNA exons encoding the central rod domain common to both lamins A/C. All of these missense mutations alter residues in the lamin A/C proteins conserved throughout evolution, implying an essential structural and/or functional role of these residues. One severely affected patient possesed two mutations, one specific to lamin A that may modify the phenotype of this patient. Mutations in LMNA were frequently identified among patients with sporadic and familial forms of EDMD. Further studies are needed to identify the factors modifying disease phenotype among patients harboring mutations within lamin A/C and to determine the effect of various mutations on lamin A/C structure and function. © 2001 Wiley‐Liss, Inc. 相似文献
4.
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. 相似文献
5.
Emery-Dreifuss muscular dystrophy (EDMD) is characterised by early contractures, slowly progressive muscle wasting and weakness with a distinctive humero-peroneal distribution and cardiac conduction defects leading to dilated cardiomyopathy. The genes known to be responsible for EDMD encode proteins associated with the nuclear envelope: the emerin and the lamins A and C. 相似文献
6.
Inhibition of extracellular signal-regulated kinase signaling to prevent cardiomyopathy caused by mutation in the gene encoding A-type lamins 总被引:2,自引:0,他引:2
Autosomal Emery–Dreifuss muscular dystrophy and relateddisorders with dilated cardiomyopathy and variable skeletalmuscle involvement are caused by mutations in LMNA, which encodesA-type nuclear lamins. How alterations in A-type lamins, intermediatefilament proteins of the nuclear envelope expressed in mostdifferentiated somatic cells, cause cardiomyopathy is only poorlyunderstood. We demonstrated previously abnormal activation ofthe extracellular signal-regulated kinase (ERK) branch of themitogen-activated protein kinase (MAPK) signaling cascade inhearts of Lmna H222P knock in mice, a model ofautosomal Emery–Dreifuss muscular dystrophy. We thereforetreated LmnaH222P/H222P mice that develop cardiomyopathy withPD98059, an inhibitor of ERK activation. Systemic treatmentof LmnaH222P/H222P mice with PD98059 inhibited ERK phosphorylationand blocked the activation of downstream genes in heart. Italso blocked increased expression of RNAs encoding natriureticpeptide precursors and proteins involved in sarcomere organizationthat occurred in placebo-treated mice. Histological analysisand echocardiography demonstrated that treatment with PD98059delayed the development of left ventricular dilatation. PD98059-treatedLmnaH222P/H222P mice had normal cardiac ejection fractions assessedby echocardiography when placebo-treated mice had a 30% decrease.These results emphasize the role of ERK activation in the developmentof cardiomyopathy caused by LMNA mutations. They further provideproof of principle for ERK inhibition as a therapeutic optionto prevent or delay heart failure in humans with Emery–Dreifussmuscular dystrophy and related disorders caused by mutationsin LMNA. 相似文献
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Nesprin-1 and -2 are involved in the pathogenesis of Emery Dreifuss muscular dystrophy and are critical for nuclear envelope integrity 总被引:3,自引:0,他引:3
Zhang Q Bethmann C Worth NF Davies JD Wasner C Feuer A Ragnauth CD Yi Q Mellad JA Warren DT Wheeler MA Ellis JA Skepper JN Vorgerd M Schlotter-Weigel B Weissberg PL Roberts RG Wehnert M Shanahan CM 《Human molecular genetics》2007,16(23):2816-2833
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. 相似文献
9.
LMNA variants cause cytoplasmic distribution of nuclear pore proteins in Drosophila and human muscle
Dialynas G Flannery KM Zirbel LN Nagy PL Mathews KD Moore SA Wallrath LL 《Human molecular genetics》2012,21(7):1544-1556
Mutations in the human LMNA gene, encoding A-type lamins, give rise to laminopathies, which include several types of muscular dystrophy. Here, heterozygous sequence variants in LMNA, which result in single amino-acid substitutions, were identified in patients exhibiting muscle weakness. To assess whether the substitutions altered lamin function, we performed in vivo analyses using a Drosophila model. Stocks were generated that expressed mutant forms of the Drosophila A-type lamin modeled after each variant. Larvae were used for motility assays and histochemical staining of the body-wall muscle. In parallel, immunohistochemical analyses were performed on human muscle biopsy samples from the patients. In control flies, muscle-specific expression of the wild-type A-type lamin had no apparent affect. In contrast, expression of the mutant A-type lamins caused dominant larval muscle defects and semi-lethality at the pupal stage. Histochemical staining of larval body wall muscle revealed that the mutant A-type lamin, B-type lamins, the Sad1p, UNC-84 domain protein Klaroid and nuclear pore complex proteins were mislocalized to the cytoplasm. In addition, cytoplasmic actin filaments were disorganized, suggesting links between the nuclear lamina and the cytoskeleton were disrupted. Muscle biopsies from the patients showed dystrophic histopathology and architectural abnormalities similar to the Drosophila larvae, including cytoplasmic distribution of nuclear envelope proteins. These data provide evidence that the Drosophila model can be used to assess the function of novel LMNA mutations and support the idea that loss of cellular compartmentalization of nuclear proteins contributes to muscle disease pathogenesis. 相似文献
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11.
Hong JS Ki CS Kim JW Suh YL Kim JS Baek KK Kim BJ Ahn KJ Kim DK 《Journal of Korean medical science》2005,20(2):283-290
Emery-Dreifuss muscular dystrophy (EDMD) and limb-girdle muscular dystrophy type 1B (LGMD1B) are characterized by cardiac dysrhythmias, late-onset cardiomyopathy, slowly progressive skeletal myopathy and contractures of the neck, elbows and ankles. The causative mutation is either in the emerin gene (X-linked recessive EDMD) or lamin A/C gene (autosomal dominant EDMD2 or LGMD1B). We report three cases of EDMD, EDMD2 and LGMD1B. A 14-yr-old boy showed limitation of cervical flexion and contractures of both elbows and ankles. Sinus arrest with junctional escape beats was noted. He was diagnosed as X-linked recessive EDMD (MIM 310300). A 28-yr-old female showed severe wasting and weakness of humeroperoneal muscles. Marked limitation of cervical flexion and contractures of both elbows and ankles were noted. Varying degrees of AV block were noted. She was diagnosed as autosomal dominant EDMD2 (MIM 181350). A 41-yr-old female had contractures of both ankles and limb-girdle type muscular dystrophy. ECG revealed atrial tachycardia with high grade AV block. She was diagnosed as autosomal dominant LGMD1B (MIM 159001). Cardiac dysrhythmias in EDMD and LGMD1B include AV block, bradycardia, atrial tachycardia, atrial fibrillation, and atrial standstill, causing sudden death necessitating pacemaker implantation. Cardiologists should know about these unusual genetic diseases with conduction defects, especially in young adults. 相似文献
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Delbarre E Tramier M Coppey-Moisan M Gaillard C Courvalin JC Buendia B 《Human molecular genetics》2006,15(7):1113-1122
Hutchinson-Gilford progeria syndrome (HGPS) is a dominant autosomal premature aging syndrome caused by the expression of a truncated prelamin A designated progerin (Pgn). A-type and B-type lamins are intermediate filament proteins that polymerize to form the nuclear lamina network apposed to the inner nuclear membrane of vertebrate somatic cells. It is not known if in vivo both type of lamins assemble independently or co-assemble. The blebbing and disorganization of the nuclear envelope and adjacent heterochromatin in cells from patients with HGPS is a hallmark of the disease, and the ex vivo reversal of this phenotype is considered important for the development of therapeutic strategies. Here, we investigated the alterations in the lamina structure that may underlie the disorganization caused in nuclei by Pgn expression. We studied the polymerization of enhanced green fluorescent protein- and red fluorescent protein-tagged wild-type and mutated lamins in the nuclear envelope of living cells by measuring fluorescence resonance energy transfer (FRET) that occurs between the two fluorophores when tagged lamins interact. Using time domain fluorescence lifetime imaging microscopy that allows a quantitative analysis of FRET signals, we show that wild-type lamins A and B1 polymerize in distinct homopolymers that further interact in the lamina. In contrast, expressed Pgn co-assembles with lamin B1 and lamin A to form a mixed heteropolymer in which A-type and B-type lamin segregation is lost. We propose that such structural lamina alterations may be part of the primary mechanisms leading to HGPS, possibly by impairing functions specific for each lamin type such as nuclear membrane biogenesis, signal transduction, nuclear compartmentalization and gene regulation. 相似文献
15.
Mutations in Emery-Dreifuss muscular dystrophy and their effects on emerin protein expression 总被引:2,自引:1,他引:2
Manilal S; Recan D; Sewry CA; Hoeltzenbein M; Llense S; Leturcq F; Deburgrave N; Barbot J; Man N; Muntoni F; Wehnert M; Kaplan J; Morris GE 《Human molecular genetics》1998,7(5):855-864
Seventeen families with Emery-Dreifuss muscular dystrophy (EDMD) have been
studied both by DNA sequencing and by emerin protein expression. Fourteen
had mutations in the X-linked emerin gene, while three showed evidence of
autosomal inheritance. Twelve of the 14 emerin mutations caused early
termination of translation. An in-frame deletion of six amino acids from
the C-terminal transmembrane helix caused almost complete absence of emerin
from muscle with no localization to the nuclear membrane, although mRNA
levels were normal. This shows that mutant emerin proteins are unstable if
they are unable to integrate into a membrane. A 22 bp deletion in the
promoter region was expected to result in reduced emerin production, but
normal amounts of emerin of normal size were found in leucocytes and
lymphoblastoid cell lines. This shows that DNA analysis is necessary to
exclude emerin mutations in suspected X-linked EDMD. Emerin levels in
female carriers often deviated from the expected 50% and this was due, in
at least two families, to skewed emerin mRNA expression from the normal and
mutated alleles. In one family with a novel deletion of the last three
exons of the emerin gene, a carrier had a cardiomyopathy and very low
emerin levels (<5% of normal) due to skewed X-inactivation. In the three
autosomal cases of EDMD, emerin was normal on western blots of blood cells,
which suggests that autosomal EDMD is not caused by indirect reduction of
emerin levels.
相似文献
16.
JC Choi A Muchir W Wu S Iwata S Homma JP Morrow HJ Worman 《Science translational medicine》2012,4(144):144ra102
Mutations in the lamin A/C gene (LMNA), which encodes A-type lamins, cause a diverse range of diseases collectively called laminopathies, the most common of which is dilated cardiomyopathy. Emerging evidence suggests that LMNA mutations cause disease by altering cell signaling pathways, but the specific mechanisms are poorly understood. We show that the AKT-mammalian target of rapamycin pathway is hyperactivated in hearts of mice with cardiomyopathy caused by Lmna mutation and that in vivo administration of the rapamycin analog temsirolimus prevents deterioration of cardiac function. We also show defective autophagy in hearts of these mice and demonstrate that improvement in heart function induced by pharmacological interventions is correlated with enhanced autophagy. These findings provide a rationale for treatment of LMNA cardiomyopathy with rapalogs and implicate defective autophagy as a pathogenic mechanism of cardiomyopathy arising from LMNA mutation. 相似文献
17.
Emery-Dreifuss muscular dystrophy (EDMD) is a common form of muscular dystrophy frequently involving cardiac muscle, thus leading to dilated cardiomyopathy. Clinical outcome and prognosis is frequently determined by the involvement of the cardiac conduction system causing symptomatic bradyarrhythmias, as well as tachyarrhythmias and, if untreated, frequent sudden cardiac death. Typical features of the cardiac involvement of EDMD are presented, caused by a novel missense mutation in the splice receptor sequence of intron 6 of the LMNA gene on chromosome 1, encoding for the lamin A/C gene, consistent with the autosomal dominant form of EDMD. 相似文献
18.
FJ Ramos SC Chen MG Garelick DF Dai CY Liao KH Schreiber VL Mackay EH An R Strong WC Ladiges PS Rabinovitch M Kaeberlein BK Kennedy 《Science translational medicine》2012,4(144):144ra103
Mutations in LMNA, the gene that encodes A-type lamins, cause multiple diseases including dystrophies of the skeletal muscle and fat, dilated cardiomyopathy, and progeria-like syndromes (collectively termed laminopathies). Reduced A-type lamin function, however, is most commonly associated with skeletal muscle dystrophy and dilated cardiomyopathy rather than lipodystrophy or progeria. The mechanisms underlying these diseases are only beginning to be unraveled. We report that mice deficient in Lmna, which corresponds to the human gene LMNA, have enhanced mTORC1 (mammalian target of rapamycin complex 1) signaling specifically in tissues linked to pathology, namely, cardiac and skeletal muscle. Pharmacologic reversal of elevated mTORC1 signaling by rapamycin improves cardiac and skeletal muscle function and enhances survival in mice lacking A-type lamins. At the cellular level, rapamycin decreases the number of myocytes with abnormal desmin accumulation and decreases the amount of desmin in both muscle and cardiac tissue of Lmna(-/-) mice. In addition, inhibition of mTORC1 signaling with rapamycin improves defective autophagic-mediated degradation in Lmna(-/-) mice. Together, these findings point to aberrant mTORC1 signaling as a mechanistic component of laminopathies associated with reduced A-type lamin function and offer a potential therapeutic approach, namely, the use of rapamycin-related mTORC1 inhibitors. 相似文献
19.
Cartegni L; di Barletta MR; Barresi R; Squarzoni S; Sabatelli P; Maraldi N; Mora M; Di Blasi C; Cornelio F; Merlini L; Villa A; Cobianchi F; Toniolo D 《Human molecular genetics》1997,6(13):2257-2264
Emery-Dreifuss muscular dystrophy (EDMD) is an X-linked inherited disease
characterized by early contracture of the elbows, Achilles tendons and
post-cervical muscles, slow progressive muscle wasting and weakness and
cardiomyopathy presenting with arrhythmia and atrial paralysis: heart block
can eventually lead to sudden death. The EDMD geneencodes a novel
ubiquitous protein, emerin, which decorates the nuclear rim of many cell
types. Amino acid sequence homology and cellular localization suggested
that emerin is a member of the nuclear lamina-associated protein family.
These findings did not explain the role of emerin nor account for the
skeletal muscle- and heart-specific clinical manifestations associated with
the disorder. Now we report that emerin localizes to the inner nuclear
membrane, via its hydrophobic C-terminal domain, but that in heart and
cultured cardiomyocytes it is also associated with the intercalated discs.
We propose a general role for emerin in membrane anchorage to the
cytoskeleton. In the nuclear envelope emerin plays a ubiquitous and
dispensable role in association of the nuclear membrane with the lamina. In
heart its specific localization to desmosomes and fasciae adherentes could
account for the characteristic conduction defects described in patients.
相似文献
20.
Mouse model carrying H222P-Lmna mutation develops muscular dystrophy and dilated cardiomyopathy similar to human striated muscle laminopathies 总被引:12,自引:0,他引:12
Arimura T Helbling-Leclerc A Massart C Varnous S Niel F Lacène E Fromes Y Toussaint M Mura AM Keller DI Amthor H Isnard R Malissen M Schwartz K Bonne G 《Human molecular genetics》2005,14(1):155-169
Laminopathies are a group of disorders caused by mutations in the LMNA gene encoding A-type lamins, components of the nuclear lamina. Three of these disorders affect specifically the skeletal and/or cardiac muscles, and their pathogenic mechanisms are still unknown. We chose the LMNA H222P missense mutation identified in a family with autosomal dominant Emery-Dreifuss muscular dystrophy, one of the striated muscle-specific laminopathies, to create a faithful mouse model of this type of laminopathy. The mutant mice exhibit overtly normal embryonic development and sexual maturity. At adulthood, male homozygous mice display reduced locomotion activity with abnormal stiff walking posture and all of them die by 9 months of age. As for cardiac phenotype, they develop chamber dilation and hypokinesia with conduction defects. These abnormal skeletal and cardiac features were also observed in the female homozygous mice but with a later-onset than in males. Histopathological analysis of the mice revealed muscle degeneration with fibrosis associated with dislocation of heterochromatin and activation of Smad signalling in heart and skeletal muscles. These results demonstrate that LmnaH222P/H222P mice represent a good model for studying laminopathies affecting striated muscles as they develop a dystrophic condition of both skeletal and cardiac muscles similar to the human diseases. 相似文献