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1.
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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2.
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
3.
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
4.
ERG phenotype of a dystrophin mutation in heterozygous female carriers of Duchenne muscular dystrophy
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Fitzgerald KM Cibis GW Gettel AH Rinaldi R Harris DJ White RA 《Journal of medical genetics》1999,36(4):316-322
PURPOSE: Mutations in the dystrophin gene result in Duchenne muscular dystrophy (DMD). DMD is associated with an abnormal electroretinogram (ERG) if the mutation disrupts the translation of retinal dystrophin (Dp260). Our aim was to determine if incomplete ERG abnormalities would be associated with heterozygous carriers of dystrophin gene mutations. METHODS: Ganzfeld ERGs were obtained under scotopic and photopic testing conditions from a family which includes the heterozygous maternal grandmother, the heterozygous mother, and her children, two affected boys and dizygotic twin sibs, an unaffected male and heterozygous female. Southern blot analyses were done to characterise the dystrophin mutation. RESULTS: The dystrophin gene was found to contain a deletion encompassing exon 50. The ERGs in the two affected boys were abnormal, consistent with the DMD ERG phenotype. Serial ERGs of the heterozygous females were abnormal; however, they were less severely affected than the DMD boys. The ERG of the female sib showed a greater abnormality than her mother and maternal grandmother. The unaffected twin had a normal ERG. CONCLUSIONS: The ERG shows abnormalities associated with carrier status in this family with a single exon deletion. A large study of confirmed obligate carriers is planned to clarify further the value of the ERG in detecting female heterozygous carriers of dystrophin gene mutations. 相似文献
5.
目的 研究进行性肌营养不良(Duchenne/Becker muscular dystrophy,DMD/BMD)患者视网膜眼电图(electroretinogram,ERG)表型与临床分型以及基因型的关系。进一步探讨不同基因型的DMD患者抗肌营养不良蛋白(dystrophin)及其同源蛋白在视网膜上的表面爱功能,揭示DMD出现ERG异常的分子机理,方法 用11对引物对22例临床确诊的DMD/BMD患者作三步多重PCR进行基因缺失分析,并行ERG检查,结果 DMD/BMD患者ERG改变与临床分型及病情严重程度无关,与DMD/BMD的基因型有关,基因中央区缺失型的ERG异常率明显高于基因非缺失型,结论 DMD/BMD的ERG改变与DMD基因突变位点有关,可能DP260转录启动子与视网膜电信号的传导关系最密切。 相似文献
6.
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
7.
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
8.
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
9.
Adeline Vulin Nicolas Wein Dana M. Strandjord Eric K. Johnson Andrew R. Findlay Baijayanta Maiti Michael T. Howard Yuuki J. Kaminoh Laura E. Taylor Tabatha R. Simmons Will C. Ray Federica Montanaro Jim M. Ervasti Kevin M. Flanigan 《Human mutation》2014,35(2):257-264
Duchenne muscular dystrophy (DMD) is associated with the loss of dystrophin, which plays an important role in myofiber integrity via interactions with β‐dystroglycan and other members of the transmembrane dystrophin‐associated protein complex. The ZZ domain, a cysteine‐rich zinc‐finger domain near the dystrophin C‐terminus, is implicated in forming a stable interaction between dystrophin and β‐dystroglycan, but the mechanism of pathogenesis of ZZ missense mutations has remained unclear because not all such mutations have been shown to alter β‐dystroglycan binding in previous experimental systems. We engineered three ZZ mutations (p.Cys3313Phe, p.Asp3335His, and p.Cys3340Tyr) into a short construct similar to the Dp71 dystrophin isoform for in vitro and in vivo studies and delineated their effect on protein expression, folding properties, and binding partners. Our results demonstrate two distinct pathogenic mechanisms for ZZ missense mutations. The cysteine mutations result in diminished or absent subsarcolemmal expression because of protein instability, likely due to misfolding. In contrast, the aspartic acid mutation disrupts binding with β‐dystroglycan despite an almost normal expression at the membrane, confirming a role for the ZZ domain in β‐dystroglycan binding but surprisingly demonstrating that such binding is not required for subsarcolemmal localization of dystrophin, even in the absence of actin binding domains. 相似文献
10.
Duchenne muscular dystrophy: negative electroretinograms and normal dark adaptation. Reappraisal of assignment of X linked incomplete congenital stationary night blindness. 总被引:1,自引:1,他引:1
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Aland Island eye disease (AIED) and X linked congenital stationary night blindness (CSNB) have been mapped to Xp11.3. Patients have been described with deletions of the Duchenne muscular dystrophy (DMD) gene who also had a negative electroretinogram (ERG) similar to that seen in patients with CSNB and AIED. This seems to confirm that some cases of AIED and CSNB map to Xp21. We examined 16 boys with DMD/BMD (Becker muscular dystrophy) of whom 10 had negative ERGs, eight of them having deletions downstream from exon 44. Normal dark adaptation thresholds were observed in all patients and there were no anomalous visual functions. Hence, CSNB cannot be assigned to Xp21 and negative ERG in DMD/BMD is not associated with eye disease. Six boys with DMD/BMD had normal ERGs. We speculate that a retinal or glial dystrophin may be truncated or absent in the boys with negative ERGs. 相似文献
11.
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
12.
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
13.
14.
Analysis of Dystrophin Gene Deletions by Multiplex PCR in Moroccan Patients 总被引:4,自引:0,他引:4
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Duchenne and Becker muscular dystrophy (DMD and BMD) are X-linked diseases resulting from a defect in the dystrophin gene located on Xp21. DMD is the most frequent neuromuscular disease in humans (1/3500 male newborn). Deletions in the dystrophin gene represent 65% of mutations in DMD/BMD patients. We have analyzed DNA from 72 Moroccan patients with DMD/BMD using the multiplex polymerase chain reaction (PCR) to screen for exon deletions within the dystrophin gene, and to estimate the frequency of these abnormalities. We found dystrophin gene deletions in 37 cases. Therefore the frequency in Moroccan DMD/BMD patients is about 51.3%. All deletions were clustered in the two known hot-spots regions, and in 81% of cases deletions were detected in the region from exon 43 to exon 52. These findings are comparable to those reported in other studies. It is important to note that in our population, we can first search for deletions of DMD gene in the most frequently deleted exons determined by this study. This may facilitate the molecular diagnosis of DMD and BMD in our country. 相似文献
15.
16.
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
17.
《Journal of neurogenetics》2013,27(4):170-175
AbstractDuchenne and Becker muscular dystrophies (DMD/BMD) are the most common inherited muscle diseases caused by mutations in the dystrophin gene. The reading frame rule explains the genotype-phenotype relationship in DMD/BMD. In Vietnam, extensive mutation analysis has never been conducted in DMD/BMD. Here, 152 Vietnamese muscular dystrophy patients were examined for dystrophin exon deletion by amplifying 19 deletion-prone exons and deletion ends were confirmed by dystrophin cDNA analysis if necessary. The result was that 82 (54%) patients were found to have exon deletions, thus confirming exact deletion ends. A further result was that 37 patterns of deletion were classified. Deletions of exons 45–50 and 49–52 were the most common patterns identified, numbering six cases each (7.3%). The reading frame rule explained the genotype-phenotype relationship, but not five (6.1%) DMD cases. Each of five patients had deletions of exons 11–27 in common. The applicability of the therapy producing semifunctional in frame mRNA in DMD by inducing skipping of a single exon was examined. Induction of exon 51 skipping was ranked at top priority, since 16 (27%) patients were predicted to have semifunctional mRNA skipping. Exons 45 and 53 were the next ranked, with 12 (20%) and 11 (18%) patients, respectively. The largest deletion database of the dystrophin gene, established in Vietnamese DMD/BMD patients, disclosed a strong indication for exon-skipping therapy. 相似文献
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