Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Dystrophin is present in the outer plexiform layer of the retina and is required for normal retinal function as measured by electroretinography. We describe the identification of a novel isoform of dystrophin (Dp260) present in the mouse retina. The unique 5' terminus of the mRNA originates from a newly identified exon and is spliced in frame to exon 30 of the Duchenne muscular dystrophy (DMD) gene. The retinal isoform of dystrophin has 13 novel amino acids as its N-terminus followed by most of the dystrophin rod domain and the cysteine-rich C-terminal domains. Analysis of mouse tissues indicated this isoform of dystrophin is expressed in retina, brain and cardiac tissue. Comparison of retinal electrophysiology in mdx and mdxCv3 mouse suggests that Dp260 is required for normal retinal function.
Hum Mol Genet 1995 May
PMID:A novel dystrophin isoform is required for normal retinal electrophysiology. 763 43

We have identified a 7.5 kb transcript from the dystrophin locus which encodes a novel 140 kDa protein (Dp140). Based on immunoblotting Dp140 consists of the distal rod domain and C-terminus of 427 kDa dystrophin and is found throughout the CNS. This protein is transcribed from an alternative promoter in the dystrophin locus upstream to exon 45. The unique 5' first exon is conserved between rat and human. The transcript has a 1 kb 5' untranslated region, and the first methionine initiation codon occurs in exon 51, predicting a protein of 140 kDa. Several studies report that Duchenne dystrophy patients with deletions in the exon 45-52 region have an increased incidence of cognitive impairment. Such deletions would affect expression of 427 kDa dystrophin and this shorter 140 kDa isoform but not the recently described small distal transcripts Dp116 or Dp71, suggesting particular importance to CNS function.
Hum Mol Genet 1995 Mar
PMID:Dp140: a novel 140 kDa CNS transcript from the dystrophin locus. 779 84

Duchenne muscular dystrophy (DMD) is accompanied by varying degrees of mental retardation. The molecular basis for this is unknown, although at least four dystrophin transcripts regulated by specific promoters and undergoing elaborate splicing control are present in brain areas associated with cognitive function. In muscle the absence of dystrophin causes instability of a dystrophin-associated protein complex (DAPC) linking the cytoskeleton to the extracellular matrix; this disruption is accompanied by muscle necrosis. The laminin-binding component of DAPC, dystroglycan, in contrast to other components of DAPC, has been found in brain homogenates. This suggests that the link between the membrane cytoskeleton and extracellular matrix mediated by dystrophin-dystroglycan may play a functional role in brain. We have cloned a mouse dystroglycan partial cDNA and have mapped this gene in the mouse to chromosome 9. Further, in situ hybridisation to mouse brain sections shows that the dystroglycan gene is expressed in relatively few structures and co-localises with dystrophin mRNA in hippocampus, dentate gyrus, olfactory bulb and Purkinje neurons but, surprisingly, not in the cortex. Dystroglycan is also expressed in those brain areas where the dystrophin-related protein (utrophin) is present. Our results provide a basis for a future characterisation of the role of dystrophin-dystroglycan association in the brain.
Hum Mol Genet 1994 Sep
PMID:Dystroglycan: brain localisation and chromosome mapping in the mouse. 783 16

The C-terminal domain of dystrophin is alternatively spliced to produce a variety of tissue and developmental stage-specific isoforms. Recent studies suggest that the C-terminal domain binds to the dystrophin-associated glycoprotein complex (DGC) in muscle, but little is known about the functional significance of the alternative splicing or what role individual isoforms may play in specific tissues. The major dystrophin transcript in brain lacks exons 71-74, and encodes an isoform not observed in skeletal muscle. To explore the capacity of this truncated isoform to function in muscle, we have generated transgenic mice expressing a murine dystrophin mini-gene missing exons 71-74. Uniform expression of this construct on a mutant mdx mouse background results in normal muscle morphology and physiology, and prevents the development of muscular dystrophy. These mice also display normal expression and localization of the DGC, suggesting that the alternatively spliced exons are not required for dystrophin function in skeletal muscle. An additional line of mice was analyzed that had a mosaic pattern of expression. These mice display a markedly milder phenotype than mdx mice, despite the expression of dystrophin in only half the muscle fibers. These results indicate that viral delivery of dystrophin to a simple majority of fibers in a muscle group would greatly reduce the dystrophic pathology associated with Duchenne muscular dystrophy.
Hum Mol Genet 1994 Oct
PMID:Prevention of dystrophic pathology in mdx mice by a truncated dystrophin isoform. 784 95

A lack of dystrophin results in muscle degeneration in Duchenne muscular dystrophy. Dystrophin-deficient human and mouse muscle cells have higher resting levels of intracellular free calcium ([Ca2+]i) and show a related increase in single-channel open probabilities of calcium leak channels. Elevated [Ca2+]i results in high levels of calcium-dependent proteolysis, which in turn increases calcium leak channel activity. This process could initiate muscle degeneration by further increasing [Ca2+]i and proteolysis in a positive feedback loop. Here, we tested the direct effect of restoration of dystrophin on [Ca2+]i and channel activity in primary myotubes from mdx mice made transgenic for full-length dystrophin. Transgenic mdx mice have been previously shown to have normal dystrophin localization and no muscle degeneration. Fura-2 calcium measurements and single-channel patch recordings showed that resting [Ca2+]i levels and open probabilities of calcium leak channels of transgenic mdx myotubes were similar to normal levels and significantly lower than mdx littermate controls (mdx) that lack dystrophin. Thus, restoration of normal calcium regulation in transgenic mdx mice may underlie the resulting absence of degeneration.
Mol Biol Cell 1994 Oct
PMID:Myotubes from transgenic mdx mice expressing full-length dystrophin show normal calcium regulation. 786 81

The largest in-frame deletion in the dystrophin gene previously reported in a BMD patient encompasses exons 17 to 48, which corresponds to 46% of the coding region. Here we report a larger deletion of exons 13 to 48 in a 37 year-old BMD patient with a mild phenotype. Such deletion, which corresponds to 50% of the coding region is the largest reported so far associated with a benign clinical course. Dystrophin assessment (through immunofluorescence and Western blot) using antibodies against different regions of the dystrophin was concordant with his deletion. The observation of this patient has important implication for gene therapy trials based on minigenes, since it confirms that deletions of up to 66% of the rod domain are compatible with a mild phenotype.
Hum Mol Genet 1994 Jun
PMID:Half the dystrophin gene is apparently enough for a mild clinical course: confirmation of its potential use for gene therapy. 795 Dec 37

Two promoters in the distal half of the Duchenne Muscular Dystrophy gene drive transcription of mRNAs which have novel first exons and encode the shortened forms of dystrophin, apo-dystrophin-1 (Dp71) and apo-dystrophin-2 (Dp116). Apo-dystrophin-1 has a G + C rich promoter and is expressed in a wide range of cell types, whilst apo-dystrophin-2 is confined to peripheral nerve and brain. We have isolated and sequenced the unique 5' exon of rat apo-dystrophin-2 mRNA. Conceptual translation of this sequence indicates that apo-dystrophin-2 contains a unique 23 amino acid terminal peptide. Using specific probes derived from sequences at the 5' ends of apo-dystrophin-1 and apo-dystrophin-2 we have determined the expression of these two mRNAs during mouse embryonic development by RNA in situ hybridization. In contrast to full-length dystrophin, neither of these short dystrophin transcripts appear before organogenesis is well established. Apo-dystrophin-1 mRNA is detected in midline cells of the ventral neural tube and later, in the ependymal cells lining the ventricles of the brain. These results suggest that apo-dystrophin-1 mRNA is associated with glial cells in the CNS. Apo-dystrophin-1 transcripts are also abundant in the teeth primordia throughout their development. In contrast apo-dystrophin-2 mRNA is largely undetectable during development, although transcripts are seen in the newborn brain. Western blots of late human fetal tissue extracts confirm that apo-dystrophin-2 is most abundant in brain and analysis of RNA and protein in cultured cell lines reveal expression of apo-dystrophin-1 and apo-dystrophin-2 in glioma cells.
Hum Mol Genet 1994 Aug
PMID:Apo-dystrophin-1 and apo-dystrophin-2, products of the Duchenne muscular dystrophy locus: expression during mouse embryogenesis and in cultured cell lines. 798 7

Single muscle fibers from mdx mouse muscle, which is deficient in dystrophin, and control mouse muscle, containing dystrophin, were compared by scanning electron microscopy. In particular, comparisons were made of the surface morphology at myotendinous junctions and costameres, sites at the muscle cell surface that are enriched in dystrophin and where force is transmitted across the cell membrane. Muscle fibers from 4- and 6-week-old controls display nearly uniform surface morphology characterized by numerous digit-like processes at the myotendinous junction and nonjunctional surface membrane possessing distinct grooves at sites corresponding to underlying costameres. Mdx fibers at this stage showed blunted myotendinous junctions with few digit-like processes, infrequent indistinct costameric markings, and holes in the cell membrane. Cells from peak regenerating mdx muscle (6 weeks) showed surface morphology similar to 4-week mdx fibers, although the proportion of fibers displaying extensive structural defects was reduced at 6 weeks. Completely regenerated mdx fibers (23 weeks) were indistinguishable from fibers of 6-week-old mdx mice. In control mice, only approximately 6% of the fibers examined from 4- or 6-week-old mice showed any of the structural defects characteristic of the majority of mdx fibers. However, fibers from 23-week-old control mice displayed an increased frequency of cells with poorly defined junctional processes and surface striations. These findings indicate that the fibers displaying extensive disruption of surface features, which are most commonly observed in 4-week mdx mice at peak necrosis, are necrotic fibers. Specific defects, such as the reduction in myotendinous junction folding, loss of costameres, and increased occurrence of membrane holes, are observed in the majority of mdx fibers at all ages. Thus, these defects are more directly attributable to dystrophin's absence because their frequency of occurrence is independent of the stage of necrosis and regeneration.
Exp Mol Pathol 1994 Aug
PMID:Modifications in myotendinous junction surface morphology in dystrophin-deficient mouse muscle. 799 79

Approximately half of the transcripts of the DMD gene isolated from peripheral blood lymphocytes and detected by RT-PCR do not contain exon 9. This 'exon skipping' can be observed to a variable extent in all tissues not specifically expressing the gene product 'dystrophin'. The shorter transcript is rare in muscle, heart and brain. Similar results were found in mice. Since the 3' end of exon 9 reflects the consensus sequence of a 3' splice site, it is suggested that exon 9 due to this sequence element is 'recognized' as an intron and removed from an RNA intermediate. This model is supported by a mathematical comparison of real and putative splice sites within the gene.
Hum Mol Genet 1994 Feb
PMID:An explanation for the constitutive exon 9 cassette splicing of the DMD gene. 800 97

Expression of Becker-like and full-length human dystrophins was stable for at least 6 months in mdx mouse muscle following intramuscular plasmid DNA injection. Intramuscular injection of a single plasmid DNA encoding both luciferase and dystrophin resulted in stable luciferase expression for at least 2 months in mdx muscle, whereas injection of plasmid DNA encoding only luciferase did not result in stable luciferase expression. These results suggest that expression of either full-length or Becker-like dystrophins protects mdx mouse myofibers from degeneration.
Hum Mol Genet 1993 Dec
PMID:Dystrophin expression improves myofiber survival in mdx muscle following intramuscular plasmid DNA injection. 811 73


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