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1.
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
2.
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
3.
Manilal S; Sewry CA; Pereboev A; Man N; Gobbi P; Hawkes S; Love DR; Morris GE 《Human molecular genetics》1999,8(2):353-359
Emerin is a nuclear membrane protein which is missing or defective in
Emery-Dreifuss muscular dystrophy (EDMD). It is one member of a family of
lamina-associated proteins which includes LAP1, LAP2 and lamin B receptor
(LBR). A panel of 16 monoclonal antibodies (mAbs) has been mapped to six
specific sites throughout the emerin molecule using phage- displayed
peptide libraries and has been used to localize emerin in human and rabbit
heart. Several mAbs against different emerin epitopes did not recognize
intercalated discs in the heart, though they recognized cardiomyocyte
nuclei strongly, both at the rim and in intranuclear spots or channels. A
polyclonal rabbit antiserum against emerin did recognize both nuclear
membrane and intercalated discs but, after affinity purification against a
pure-emerin band on a western blot, it stained only the nuclear membrane.
These results would not be expected if immunostaining at intercalated discs
were due to a product of the emerin gene and, therefore, cast some doubt
upon the hypothesis that cardiac defects in EDMD are caused by absence of
emerin from intercalated discs. Although emerin was abundant in the
membranes of cardiomyocyte nuclei, it was absent from many non-myocyte
cells in the heart. This distribution of emerin was similar to that of
lamin A, a candidate gene for an autosomal form of EDMD. In contrast, lamin
B1 was absent from cardiomyocyte nuclei, showing that lamin B1 is not
essential for localization of emerin to the nuclear lamina. Lamin B1 is
also almost completely absent from skeletal muscle nuclei. In EDMD, the
additional absence of lamin B1 from heart and skeletal muscle nuclei which
already lack emerin may offer an alternative explanation of why these
tissues are particularly affected.
相似文献
4.
Lamin A/C and emerin are critical for skeletal muscle satellite cell differentiation 总被引:10,自引:0,他引:10
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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
5.
6.
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
7.
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
8.
9.
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. 相似文献
10.
The Emery-Dreifuss muscular dystrophy protein, emerin, is a nuclear membrane protein 总被引:13,自引:4,他引:9
A large fragment of emerin cDNA was prepared by PCR and expressed as a
recombinant protein in Escherichia coli. Using this as immunogen, we
prepared a panel of 12 monoclonal antibodies which recognise at least four
different epitopes on emerin in order to ensure that emerin can be
distinguished from non-specific cross-reacting proteins. All the mAbs
recognised a 34 kDa protein in all tissues tested, though minor emerin-
related bands were also detected in some tissues. Immunofluorescence
microscopy showed that emerin is located at the nuclear rim in all tissues
examined. A muscle biopsy from an Emery-Dreifuss muscular dystrophy (EMDM)
patient showed complete absence of emerin by both Western blotting and
immunohistochemistry, suggesting a simple diagnostic antibody test for EDMD
families. Biochemical fractionation of brain and liver tissues showed that
emerin was present in nuclei purified by centrifugation through 65% sucrose
and was absent from soluble fractions (post-100,000 g). From these results,
together with sequence and structural homologies between emerin,
thymopoietins and the nuclear lamina-associated protein, LAP2, we suggest
that emerin will prove to be one member of a family of inner nuclear
membrane proteins.
相似文献
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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13.
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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15.
Brown CA Scharner J Felice K Meriggioli MN Tarnopolsky M Bower M Zammit PS Mendell JR Ellis JA 《Journal of human genetics》2011,56(8):589-594
Emery-Dreifuss muscular dystrophy (EDMD) is a neuromuscular disorder exhibiting a cardiomyopathy with cardiac conduction defects. X-linked EDMD arises from mutations in the EMD gene, which encodes for a nuclear membrane protein termed emerin. In this study, we describe novel and recurrent EMD mutations identified in 18 probands and three carriers from a cohort of 255 North American patients referred for EDMD genetic mutation analysis. Eight of these mutations are novel including six frameshift mutations (p.D9GfsX24, p.F39SfsX17, p.R45KfsX16, p.F190YfsX19, p.R203PfsX34 and p.R204PfsX7) and two non-sense mutations (p.S143X, p.W200X). Our data augment the number of EMD mutations by 13.8%, equating to an increase of 5.2% in the total known EMD mutations and to an increase of 6.0% in the number of different mutations. Analysis of the exon distribution of mutations within the EMD gene, suggests a nonrandom distribution, with exon 2 as a hot spot. This phenomenon may be due to its high GC content, which at 60% is the most GC-rich exon in the EMD gene. 相似文献
16.
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
17.
Very recently, mutations within the LMNA gene on chromosome 1q21.2 were shown to result in forms of muscular dystrophy, conduction-system disease, cardiomyopathy, and partial lipodystrophy. The LMNA gene encodes for the nucleophilic A-type lamins, lamin A and lamin C. These isoforms are generated by different splicing within exon 10 of LMNA. Thus lamin A/C is, besides emerin, the first known nucleophilic protein which plays a role in human disease. To date, 41 different mutations, predominantly missense, in the LMNA gene are known causing variable phenotypes. Twenty-three different mutations of LMNA have so far been shown to cause autosomal-dominant Emery-Dreifuss muscular dystrophy (EDMD2), three mutations were reported to cause limb-girdle muscular dystrophy (LGMD1B), eight mutations are known to result in dilated cardiomyopathy (CMD1A), and seven mutations were reported to cause familial partial lipodystrophy (FPL). The reports of lamin mutations including the corresponding phenotype are of great interest in order to gain insights into the function of lamin A/C. Here we summarize the mutations published to date in LMNA encoding lamin A/C. 相似文献
18.
Identification of new mutations in the Emery-Dreifuss muscular dystrophy gene and evidence for genetic heterogeneity of the disease 总被引:1,自引:0,他引:1
Blone Silvia; Small Kersten; Aksmanovic Veronica M.A.; D'Urso Michele; Ciccodicola Alfredo; Merlini Luciano; Morandi Lucia; Kress Wolfram; Yates John R.W.; Warren Steve T.; Toniolo Daniela 《Human molecular genetics》1995,4(10):1859-1863
19.
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
20.
Wang Jieying Tetsuo Kondo Tetsu Yamane Tadao Nakazawa Naoki Oishi Tomonori Kawasaki Kunio Mochizuki Niu Dongfeng Ryohei Katoh 《ACTA HISTOCHEMICA ET CYTOCHEMICA》2014,47(6):289-294
Emerin is a LEM domain-containing integral membrane protein of the vertebrate nuclear envelope. Recently it has been reported that emerin regulates tissue-specific gene/protein expression. We studied the relationship between emerin expression and follicle function in normal and hyperplastic human thyroid tissues using immunohistochemistry and statistical methods. Emerin immunoreactivity was heterogeneous among follicular cells and follicles in normal thyroid tissue. It tended to be strong in the nuclei of tall follicular cells of small follicles and weak or negative in the nuclei of flat follicular cells of large follicles. Follicles with strong expression of emerin were also strongly positive for thyroglobulin (Tg) and thyroxine (T4) in follicular cells and colloid substance, suggesting active functioning follicles. In contrast, large follicles with weak expression of emerin were also weak or negative for Tg and T4. Emerin immunoreactivity was strong in almost all nuclei of hyperplastic follicular cells in Graves’ disease tissues. These findings suggest that emerin expression may be related with follicular function and may contribute to the understanding of hormonogenesis in normal thyroid follicles. 相似文献