共查询到20条相似文献,搜索用时 31 毫秒
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Howard PL; Dally GY; Wong MH; Ho A; Weleber RG; Pillers DA; Ray PN 《Human molecular genetics》1998,7(9):1385-1391
The electroretinograms (ERGs) of patients with Duchenne muscular dystrophy
and an allelic variant of the mdx mouse (mdxCv3) have been shown to be
abnormal. Analysis of five allelic variants of the mdx mouse with mutations
in the dystrophin gene has shown that there is a correlation between the
position of the mutation and the severity of the ERG abnormality. Three
isoforms are expressed in the retina: Dp427, Dp260 and Dp71. Using indirect
immunofluorescence and isoform-specific antibodies on retinal sections from
three allelic mdx mouse strains, we have examined the localization of each
of the isoforms. We show that Dp71 expression does not overlap with Dp427
and Dp260 expression at the outer plexiform layer (OPL). Instead, Dp71 is
localized to the inner limiting membrane (ILM) and to retinal blood
vessels. Moreover, we show that Dp260 and Dp71 differ structurally at their
respective C-termini. In addition, we find that the proper localization of
the beta- dystroglycan is dependent upon both Dp260 at the OPL and Dp71
expression at the ILM. Thus, Dp260 and Dp71 are non-redundant isoforms that
are located at different sites within the retina yet have a common
interaction with beta-dystroglycan. Our data suggest that both Dp71 and
Dp260 contribute distinct but essential roles to retinal electrophysiology.
相似文献
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Kameya S; Araki E; Katsuki M; Mizota A; Adachi E; Nakahara K; Nonaka I; Sakuragi S; Takeda S; Nabeshima Y 《Human molecular genetics》1997,6(13):2195-2203
Dp260 is a C-terminal isoform of dystrophin and is expressed specifically
in the retina. Abnormal electroretinograms (ERG) in some Duchenne muscular
dystrophy (DMD) and Becker muscular dystrophy (BMD) patients are likely
linked to a disruption of Dp260. To clarify the importance of Dp260 in the
retina, we examined dystrophin exon 52 knock- out mice, whose expression of
Dp260 is impaired. We also confirmed the localization of Dp260 in the outer
plexiform layer (OPL) of the retina. Disruption of Dp260 causes a change in
the localization of beta- dystroglycan, which is normally found in the OPL
of the retina. This suggests a requirement for Dp260 for normal formation
of the dystrophin- dystroglycan complex in the retina. Dp71, also expressed
in the retina, was, however, not detected in the OPL. The difference in
localization of Dp260 and Dp71 implies that the two isoforms have different
functions. The dystrophin exon 52 knock-out mice had a prolonged implicit
time of the b-wave in ERG, although no significant change was observed in
amplitude. These ERG findings differed from those of DMD and BMD patients,
especially with regard to amplitude of the b-wave, but make it clear that
Dp260 is required for normal electrophysiology.
相似文献
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Pillers DA Weleber RG Green DG Rash SM Dally GY Howard PL Powers MR Hood DC Chapman VM Ray PN Woodward WR 《Molecular genetics and metabolism》1999,66(2):100-110
Duchenne and Becker muscular dystrophy patients have mutations in the dystrophin gene. Most show reduced b-wave amplitudes in the dark-adapted electroretinogram (ERG). We studied normal C57BL/6J mice and five X-linked muscular dystrophy strains with different dystrophin mutations to determine whether the location of the mutation within the gene affects the mouse ERG and to correlate such effects with dystrophin isoform expression. Amplitudes and implicit times were measured for a-waves, b-waves, and digitally filtered oscillatory potentials. mdx and mdxCv5 mice, with mutations near the amino terminus and lacking expression of Dp427, had ERGs similar to those of C57BL/6J mice. mdxCv2 and mdxCv4 mice, with mutations in the center of dystrophin and who do not express isoforms Dp427, Dp260, or Dp140 (mdxCv4), had increased b-wave and oscillatory potential implicit times. mdxCv3 mice, with a mutation near the carboxy terminus resulting in deficiency of all dystrophin isoforms, had increased b-wave and oscillatory potential implicit times and reduced scotopic b-wave amplitudes. Fitting the a-wave data to a transduction activation phase mathematical model showed normal responses for all phenotypes, suggesting that the b-wave delays are due to defects beyond the rod outer segment, most likely at the rod to on-bipolar cell synapse. The variation in the ERG phenotype with the position of the dystrophin gene mutation suggests that there are different contributions by each isoform to retinal electrophysiology. Although Dp427 and Dp140 isoforms do not appear to be important contributors to the ERG, lack of Dp260 and possibly Dp71 isoforms is associated with an abnormal ERG. 相似文献
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Greenberg DS; Schatz Y; Levy Z; Pizzo P; Yaffe D; Nudel U 《Human molecular genetics》1996,5(9):1299-1303
Duchenne muscular dystrophy (DMD) is a progressive degenerative lethal
muscle disease. A significant proportion of DMD affected children suffer
also from mental retardation. The rod shaped protein, dystrophin, which is
absent from or defective in the muscle of DMD patients, binds to a number
of membrane associated proteins (known collectively as dystrophin
associated proteins [DAPs]). The levels of DAPs is greatly reduced in the
muscle of DMD patients and mdx mice, which lack dystrophin. In addition to
dystrophin isoforms, the DMD gene codes also for several smaller proteins.
One of the small proteins, Dp71, is expressed in most or all non-muscle
tissues and is the major DMD gene product in the brain. The function of the
small DMD gene products is unknown. Here we show that mutant mice which do
not express the smaller non-muscle products of the DMD gene have a reduced
level of DAPs in their brain. This suggests that Dp71 is important for the
formation and/or stabilization of a DAPs complex in brain.
相似文献
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Dp140: a novel 140 kDa CNS transcript from the dystrophin locus 总被引:6,自引:10,他引:6
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Labarque V Freson K Thys C Wittevrongel C Hoylaerts MF De Vos R Goemans N Van Geet C 《Human molecular genetics》2008,17(3):357-366
Controversy exists regarding the cause of the significantly increased blood loss during spinal surgery in Duchenne muscular dystrophy (DMD) patients compared with similar surgery in other patients. DMD is caused by a mutation in the cytoskeletal dystrophin, which binds to extracellular matrix laminin and which has been described as a G-protein-coupled receptor. We hypothesized that disturbed cytoskeleton organization in DMD patients would alter Gs protein and collagen signalling in platelets, leading to dysfunctional platelets and a haemorrhagic tendency during surgery. In the present study, we found that platelets and skin fibroblasts, respectively, express the Dp71 and Dp116 dystrophin isoforms. Absent or decreased expression of these isoforms in DMD patients correlates with significant Gs alpha upregulation. Moreover, dysfunctional dystrophin in these cells is accompanied with increased Gs signalling and higher cAMP levels after Gs stimulation. Functional analysis showed that DMD platelets responded slower to collagen with an extensive shape change in the aggregometer and with a significantly reduced platelet adhesion to coated collagen under flow. The decreased collagen activation was shown to result from both Gs activation and cytoskeletal disruption and not from decreased expression of platelet membrane receptors or impaired von Willebrand factor (vWF) activity. In conclusion, DMD platelets have a disorganized cytoskeleton and manifest Gs hyperactivity and reduced platelet collagen reactivity. Their increased bleeding during surgery will, at least partly, result from the increased platelet Gs activity after the release of natural Gs agonists as prostacyclin during surgery and an ineffective reactivity to collagen. 相似文献
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Nico B Paola Nicchia G Frigeri A Corsi P Mangieri D Ribatti D Svelto M Roncali L 《Neuroscience》2004,125(4):921-935
In order to ascertain whether the alterations of the blood-brain barrier (BBB) seen in adult dystrophic mdx-mice [Glia 42 (2003) 235], a human model of Duchenne muscular dystrophy (DMD), are developmentally established and correlated with other dystrophin isoforms which are localized at the glial-vascular interface, we used immunocytochemistry to investigate the expression of dystrophin isoforms (Dp71) during BBB development in mdx fetuses and in adult mice. Parallelly, we used Western blot, immunocytochemistry and immunogold electron microscopy to analyze the expression of the zonula occludens (ZO-1), aquaporin-4 (AQP4) and glial fibrillary acidic (GFAP) proteins as endothelial and glial markers, and we evaluated the integrity of the mdx BBB by means of intravascular injection of horseradish peroxidase (HRP). The results show reduced dystrophin isoforms (Dp71) in the mdx mouse compared with the control, starting from early embryonic life. Endothelial ZO-1 expression was reduced, and the tight junctions were altered and unlabeled. AQP4 and GFAP glial proteins in mdx mice also showed modifications in developmental expression, the glial vascular processes being only lightly AQP4- and GFAP-labeled compared with the controls. Confocal microscopy and HRP assays confirmed the alteration in vessel glial investment, GFAP perivascular endfoot reactivity being strongly reduced and BBB permeability increasing. These results demonstrate that a reduction in dystrophin isoforms (Dp71) at glial endfeet leads to an altered development of the BBB, whose no-closure might contribute to the neurological dysfunctions associated with DMD. 相似文献
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A sea urchin gene encoding dystrophin-related proteins 总被引:1,自引:2,他引:1
The gene which is defective in Duchenne muscular dystrophy (DMD) is the
largest known gene. The product of the gene in muscle, dystrophin, is a 427
kDa protein. The same gene encodes at least six additional products: two
non-muscle dystrophin isoforms transcribed from promoters located in the
5'-end region of the gene and four smaller proteins transcribed from
internal promoters located further downstream. Several other genes,
encoding evolutionarily related proteins, have been identified. These
include a structurally very similar gene in vertebrates encoding utrophin
(DRP1), which is closely related to dystrophin, and a number of small and
simple genes in vertebrates or invertebrates encoding proteins similar to
some of the small products of the DMD gene. We have isolated a sea urchin
gene showing very strong sequence and structural homology with the DMD and
utrophin genes. Sequence and intron/exon structure similarities suggest
that this gene is related to a precursor of both the DMD gene and the gene
encoding utrophin. The sea urchin gene has the unique complex structure of
the DMD gene. There is at least one, and possibly more, product(s)
transcribed from internal promoters, as well as a large product of >300
kDa containing at least three of the four major domains of dystrophin. The
small product seems to be evolutionarily related to Dp116, one of the small
products of the human DMD gene. Partial characterization of this gene
helped us to construct an evolutionary tree connecting the vertebrate
dystrophin gene family with related genes in invertebrates. The constructed
evolutionary tree also implies that the vertebrate small and simple
structured gene encoding a Dp71-like protein, called DRP2 , evolved from
the dystrophin/utrophin ancestral large and complex gene by a duplication
of only a small part of the gene.
相似文献
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The 70.8 kDa protein product of the distal part of the giantDuchenne muscular dystrophy (DMD) gene, Dp71, is expressed inmany cell types and tissues. Anchored PCR, primer extensionand functional analysis of transfected constructs were usedto determine the 5' end of the mRNA and characterize the promoterof this major DMD gene product. The 5' untranslated region (5'UTR)of Dp71 is transcribed from a single exon; the promoter doesnot contain a TATA box, and has a very high GC content and severalpotential Sp1 binding sites. It is located more than 2000 kb3' to the muscle and brain type dystrophin promoters and only150 kb from the 3' end of the gene, suggesting that in mostDMD patients the expression of Dp71 Is unaffected. 相似文献
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Targeted inactivation of Dp71, the major non-muscle product of the DMD gene: differential activity of the Dp71 promoter during development 总被引:2,自引:1,他引:1
Sarig R; Mezger-Lallemand V; Gitelman I; Davis C; Fuchs O; Yaffe D; Nudel U 《Human molecular genetics》1999,8(1):1-10
The dystrophin gene, which is defective in Duchenne muscular dystrophy
(DMD), also encodes a number of smaller products controlled by internal
promoters. Dp71, which consists of the two C-terminal domains of
dystrophin, is the most abundant product of the gene in non-muscle tissues
and is the major product in adult brain. To study the possible function of
Dp71 and its expression during development, we specifically inactivated the
expression of Dp71 by replacing its first and unique exon and a part of the
concomitant intron with a beta-galactosidase reporter gene. X-Gal staining
of Dp71-null mouse embryos and tissues revealed a very stage- and cell
type-specific activity of the Dp71 promoter during development and during
differentiation of various tissues, including the nervous system, eyes,
limb buds, lungs, blood vessels, vibrissae and hair follicles. High
activity of the Dp71 promoter often seemed to be associated with
morphogenic events and terminal differentiation. In some tissues the
activity greatly increased towards birth.
相似文献
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Point mutations at the carboxy terminus of the human dystrophin gene: implications for an association with mental retardation in DMD patients 总被引:3,自引:1,他引:3
Duchenne and Becker muscular dystrophies (DMD/BMD) are causedby mutations in the human dystrophin gene. About two-thirdsof DMD/BMD patients exhibit gross rearrangements in the genewhereas the mutations in the remaining one third are thoughtto be point mutations or minor structural lesions. By meansof various progressive PCR-based techniques hitherto a numberof point mutations has been described that in most cases shouldcause premature translational termination. These data indicatea particular functional importance for the C-termlnal regionof dystrophin and consequently for its gene products Dp 71 andDp 116. To screen for mlcroheterogeneities in this gene regionwe applied PCR-SSCP analysis to exons 60 79 of twenty-sixDMD/BMD patients without detectable deletions. The study identifiedseven point mutations and one intron polymorphism. Six pointmutations, found in DMD patients, should cause premature translationaltermination. One point mutation, identified in a BMD patient,results in an amino acid exchange. Five of the DMD patientsbearing a point mutation are mentally retarded suggesting thata disruption of the translational reading frame in the C-terminalregion is associated with this clinical finding in DMD cases.Therefore our data raise the possibility, that Dp 71 and/orDp 116, the C-termlnal translational products of dystrophin,may be causally involved in cases of mental retardation thatare associated with DMD. 相似文献
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Targeted inactivation of dystrophin gene product Dp71: phenotypic impact in mouse retina 总被引:2,自引:0,他引:2
Dalloz C Sarig R Fort P Yaffe D Bordais A Pannicke T Grosche J Mornet D Reichenbach A Sahel J Nudel U Rendon A 《Human molecular genetics》2003,12(13):1543-1554
The abnormal retinal neurotransmission observed in Duchenne muscular dystrophy (DMD) patients and in some genotypes of mice lacking dystrophin has been attributed to altered expression of short products of the dystrophin gene. We have investigated the potential role of Dp71, the most abundant C-terminal dystrophin gene product, in retinal electrophysiology. Comparison of the scotopic electroretinograms (ERG) between Dp71-null mice and wild-type (wt) littermates revealed a normal ERG in Dp71-null mice with no significant changes of the b-wave amplitude and kinetics. Analysis of DMD gene products, utrophin and dystrophin-associated proteins (DAPs), showed that Dp71 and utrophin were localized around the blood vessels, in the ganglion cell layer (GCL), and the inner limiting membrane (ILM). Dp71 deficiency was accompanied by an increased level of utrophin and decreased level of beta-dystroglycan localized in the ILM, without any apparent effect on the other DAPs. Dp71 deficiency was also associated with an impaired clustering of two Müller glial cell proteins-the inwardly rectifying potassium channel Kir4.1 and the water pore aquaporin 4 (AQP4). Immunostaining of both proteins decreased around blood vessels and in the ILM of Dp71-null mice, suggesting that Dp71 plays a role in the clustering and/or stabilization of the two proteins. AQP4 and Kir4.1 may also be involved in the regulation of the ischemic process. We found that a transient ischemia resulted in a greater damage in the GCL of mice lacking Dp71 than in wt mice. This finding points at a crucial role played by Dp71 in retinal function. 相似文献
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D'Souza Vinita N.; Man Nguyen thi; Morris Glenn E.; Karges Wolfram; Pillers De-Ann M.; Ray Peter N. 《Human molecular genetics》1995,4(5):837-842
Dystrophin is present in the outer plexiform layer of the retinaand is required for normal retinal function as measured by electroretinography.We describe the identification of a novel isoform of dystrophln(Dp260) present in the mouse retina. The unIque 5' terminusof the mRNA originates from a newly identified exon and is splicedin frame to exon 30 of the Duchenne muscular dystrophy (DMD)gene. The retinal isoform of dystrophln has 13 novel amino acidsas its N-terminus followed by most of the dystrophin rod domainand the cysteine-rich C-terminal domains. Analysis of mousetissues indicated this isoform of dystrophin Is expressed inretina, brain and cardiac tissue. Comparison of retinal electrophysiologyin mdx and mdxcv3 mouse suggests that Dp260 is required fornormal retinal function. 相似文献
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Dp116 is a non-muscle isoform of dystrophin that assembles the dystrophin-glycoprotein complex (DGC), but lacks actin-binding domains. To examine the functional role of the DGC, we expressed the Dp116 transgene in mice lacking both dystrophin and utrophin (mdx:utrn(-/-)). Unexpectedly, expression of Dp116 prevented the most severe aspects of the mdx:utrn(-/-) phenotype. Dp116:mdx:utrn(-/-) transgenic mice had dramatic improvements in growth, mobility and lifespan compared with controls. This was associated with increased muscle mass and force generating capacity of limb muscles, although myofiber size and specific force were unchanged. Conversely, Dp116 had no effect on dystrophic injury as determined by muscle histopathology and serum creatine kinase levels. Dp116 also failed to restore normal fiber-type distribution or the post-synaptic architecture of the neuromuscular junction. These data demonstrate that the DGC is critical for growth and maintenance of muscle mass, a function that is independent of the ability to prevent dystrophic pathophysiology. Likewise, this is the first demonstration in skeletal muscle of a positive functional role for a dystrophin protein that lacks actin-binding domains. We conclude that both mechanical and non-mechanical functions of dystrophin are important for its role in skeletal muscle. 相似文献