共查询到20条相似文献,搜索用时 31 毫秒
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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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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.
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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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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.
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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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Sara A. Tokarz Nancy M. Duncan Sean M. Rash Abbas Sadeghi Asheesh K. Dewan De-Ann M. Pillers 《Molecular genetics and metabolism》1998,65(4):272-281
Duchenne muscular dystrophy (DMD) is caused by a defect in a 427-kDa membrane-associated protein: dystrophin. The DMD gene also encodes several shorter isoforms which are believed to participate in nonmuscle manifestations of DMD, including abnormal retinal electrophysiology, dilated cardiomyopathy, mental retardation, and hearing defects. The purpose of this work was to determine the normal tissue expression of full-length dystrophin (Dp427) and the dystrophin isoforms Dp260, Dp140, Dp116, and Dp71, to aid in understanding what roles these isoforms might play in DMD nonmuscle manifestations. RT-PCR was performed on mRNA isolated from wild-type C57BL/6J mouse tissues, including brain, cardiac muscle, eye, intestine, kidney, liver, lung, skeletal muscle, spleen, stomach, testis, thymus, and uterus. RT-PCR amplification demonstrated that the isoforms were in a number of tissues which had not been revealed by previous Western and Northern blot analyses. Dp427 was expressed at equal levels in all tissues. Dp260 and Dp140 were present in all tissues tested, but the levels of expression varied. Dp116 was expressed in a subset of tissues and levels of expression varied. Dp71 was constitutively expressed in all tissues, suggesting that this isoform plays a basic role in normal tissue function. The expanded tissue distribution supports the hypothesis that dystrophin isoforms serve essential and unique functions, necessitating further investigation into their potential roles in DMD nonmuscle manifestations. 相似文献
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In the brain, utrophin is present in the choroid plexus epithelium and vascular endothelial cells, whereas the short C-terminal isoform of dystrophin (Dp71) is localized in the glial end-feet surrounding blood vessels. Both proteins serve as anchors for the so-called dystrophin-associated protein complex (DPC), composed of isoforms of syntrophin, dystroglycan and dystrobrevin. Numerous transporter proteins and channels have a polarized distribution in vascular endothelial cells and in glial end-feet, suggesting an association with the DPC. We investigated the composition and localization of the DPC in dependence on the anchoring proteins in mice lacking either utrophin (utrophin0/0) or dystrophin isoforms (mdx3Cv). Three distinct complexes were identified: (i) associated with utrophin in the basolateral membrane of the choroid plexus epithelium, (ii) associated with utrophin in vascular endothelial cells, and (iii) associated with Dp71 in the glial end-feet. Upon ablation of utrophin or Dp71, the corresponding DPCs were disrupted and no compensation of the missing protein by its homologue was observed. Association of the water channel aquaporin 4 with the glial DPC likewise was disrupted in mdx3Cv mice. These results demonstrate the essential role of utrophin and Dp71 for assembly of the DPC and suggest that these proteins contribute to the proper functioning of the cerebrospinal fluid and blood-brain barriers. 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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Roza Benabdesselam Alvaro Rendon Latifa Dorbani-Mamine Hélène Hardin-Pouzet 《Acta histochemica》2019,121(3):268-276
Dp71 is the major form of dystrophins (Dp) in the supraoptic nucleus (SON) and in the neural lobe of hypophysis (NL/HP). Dp71-null mice exhibit a hypo-osmolar status attributed to an altered osmosensitivity of the SON and to a perturbed vasopressinergic axis. Because oxytocin (OT) is implicated in osmoregulation via natriuresis, this study explored the oxytocinergic axis in Dp71-null mice after salt-loading (SL).Under normosmolar conditions, OT-mRNA expression was higher in the Dp71-null SON compared to wild-type (wt) and the OT peptide level has not changed. Dp-immunostaining was localized in astrocytes end-feet surrounding vessels in wt SON. This distribution changed in Dp71-null SON, Dp being detected in OT-soma of MCNs. nNOS and NADPH-diaphorase levels increased in the OT area of the Dp71-null SON compared to wt. In the NL/HP, OT level reduced in Dp71-null mice and Dp localization changed from pituicytes end-feet in wt SON to OT terminals in Dp71-null SON.Salt-Loading resulted in an increase of OT-mRNA and peptide levels in wt SON but had no effect in Dp71-null SON. In the NL/HP, OT content was reduced after SL. For Dp71-null mice, OT level, already low in control, was not modified by SL. Dp level was not affected by SL in the SON nor in the NL/HP.Our data confirmed the importance of Dp71 for the SON functionality in osmoregulation. The localization of Dp71 at the glial-vascular interface could be associated with SON osmosensitivity, leading to an adequate OT synthesis in the SON and release from the NL/HP upon plasmatic hyperosmolality. 相似文献
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García-Tovar CG Luna J Mena R Soto-Zárate CI Cortés R Pérez A León-Avila G Mornet D Rendón A Hernández JM 《Acta histochemica》2002,104(3):245-254
Dp71 is the most abundant product of the dmd gene in the brain. There are at least 2 isoforms derived from alternative splicing of exon 78 (Dp71d, which contains exon 78 and Dp71f, the spliced isoform) but the precise localization and function of each isoform is still unknown. In the present study, we demonstrate by RT-PCR that the Dp71f isoform is present in an astrocytoma cell line U-373 MG, and its subcellular localization was determined in the cytoplasm, particularly in perinuclear areas, with lower amounts towards the periphery but increasing in the leader borders of lamellipodia and focal complexes. Double labeling indirect immunofluorescence showed that Dp71f colocalized with actin-like beta-dystroglycan and beta-1 integrin. We also demonstrated by triple labeling that Dp71f was colocalized with actin and two members of integrin complexes, alpha-actinin and vinculin, in focal complexes. Ventral plasma membranes were enriched and in those containing focal complex proteins, we found colocalization of Dp71f, actin and vinculin. It is concluded that U-373 MG cells express Dp71f as part of lamellipodia and focal complex proteins, and possibly connected via distroglycan complexes to integrin complexes. 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
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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