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Query: UNIPROT:P06889 (Mol)
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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

Spinal muscular atrophy (SMA) is, after Duchenne muscular dystrophy, the most common neuromuscular disorder in childhood. The gene responsible for childhood SMA has been mapped to the q11.2-q13.3 region of chromosome 5. We have extended our linkage studies of SMA in the French-Canadian population to include microsatellite markers at the D5S125, D5S351, D5S435, JK53CA1/2 and MAP1B loci. These markers span about 4 cM of the SMA candidate region. We observed significant evidence for linkage between SMA and all the markers tested. The analysis of recombinant chromosomes provide evidence for the following genetic order: D5S125-D5S435-MAP1B-3'-JK53CA1/2 and places D5S351 proximal to JK53CA1/2. Furthermore, we confirm the current localization of the SMA gene distal to D5S435. Finally, we provide demonstration of significant linkage disequilibrium between childhood-onset SMA and four of the five marker loci, D5S125, D5S435, D5S351 and JK53CA1/2. Analysis of SMA-region haplotypes suggests that there may be a predominant SMA allele that is present on about 17% of SMA chromosomes in this sample of the French-Canadian population. We conclude that the observed linkage disequilibrium is likely due to genetic drift among regions of Quebec, consistent with this population's early history.
Hum Mol Genet 1994 Mar
PMID:Linkage disequilibrium analysis of childhood-onset spinal muscular atrophy (SMA) in the French-Canadian population. 801 58

PCR amplification has enabled a variety of studies to be performed on the murine dystrophin transcripts. Figure 7.12 displays a summary of the features of the murine dystrophin mRNA that have been described in this article. The location of the mutation in the original mdx mouse is indicated, as are the different spliced forms of the dystrophin transcript. Also shown are the location of various PCR primer binding sites that were used to deduce the alternative splicing pattern of the gene. It is likely that conventional cloning efforts aimed at identifying the variety of dystrophin spliced forms would have taken years to perform, particularly since several of the isoforms are expressed at levels significantly below the estimated 0.02% of total mRNA that dystrophin represents in skeletal muscle (Hoffman et al., 1987a, b). Amplification of dystrophin mRNA simplifies scanning methods for the identification of DNA sequence variations. Attempts to re-isolate and sequence the 14 kb cDNA to determine the mutation in separate strains of mdx mice are not likely to be time or cost effective. PCR enables these types of questions to be answered in a relatively short period of time, and similar types of analyses can be applied to human DMD tissues. Knowledge of the transcript diversity displayed by the dystrophin gene will enable the role of these separate isoforms to be addressed. Despite considerable effort by a variety of laboratories over the last five years, the precise functional role played by dystrophin remains unclear, and it can only be assumed that the separate isoforms act to modulate the functional role of dystrophin in separate tissues or in response to differing physiological states. PCR amplification of the dystrophin isoforms has enabled the variable regions of the transcript to be subcloned (Bies et al., 1992). These clones have been used to reintroduce the variable regions into full-length mini-gene expression vectors, which are currently being tested for functional activity through the generation of transgenic mdx mice. The transgenic mice can be easily identified through the PCR-ASO assays described in this article, and the reverse transcriptase PCR assays will enable a detailed analysis of the expression pattern of the introduced mini-genes. It is hoped that such analyses will further attempts to determine the feasibility of using gene therapy as a treatment for DMD/BMD.
Mol Cell Biol Hum Dis Ser 1993
PMID:PCR analysis of muscular dystrophy in mdx mice. 811 39

Dystrophin is a high molecular weight protein present at low abundance in skeletal, cardiac and smooth muscle and in trace amounts in brain. In skeletal muscle, dystrophin is uniformly distributed along the inner surface of the plasma membrane. Biochemical fractionation studies have shown that all detectable skeletal muscle dystrophin is tightly associated with a complex of wheat germ agglutinin (WGA)-binding and concanavalin A (Con A) binding sarcolemmal glycoproteins. Absence of dystrophin is the primary biochemical defect in patients with Duchenne muscular dystrophy and leads to segmental necrosis of their skeletal myofibers. Although present in similar amounts in normal cardiac and skeletal muscle, the absence of dystrophin from cardiac muscle has less severe effects on the survival of cardiac cells. We have therefore examined whether there are differences in the properties of cardiac and skeletal dystrophin. We report that in contrast to skeletal muscle, cardiac dystrophin is distributed between distinct pools: a soluble cytoplasmic pool, a membrane-bound pool not associated with WGA-binding glycoproteins and a membrane-bound pool associated with WGA-binding glycoproteins. Cardiac dystrophin was not associated with any Con A binding glycoproteins. Immunohistochemical localization studies in isolated ventricular myocytes reveal a distinct punctate staining pattern for dystrophin, approximating to the level of the transverse tubule/Z-line and contrasting with the uniform sarcolemmal staining reported for skeletal muscle fibers. The distinct properties of cardiac dystrophin suggest unique roles for this protein in cardiac versus skeletal muscle function.
Mol Cell Biochem 1994 Jan 12
PMID:Dystrophin predominantly localizes to the transverse tubule/Z-line regions of single ventricular myocytes and exhibits distinct associations with the membrane. 819 Jan 21

We have recently demonstrated the specific deficiency for the 50 kDa dystrophin-associated glycoprotein (50DAG) in Algerian patients afflicted with severe childhood autosomal recessive muscular dystrophy with DMD-like phenotype (SCARMD). A similar disease affecting Tunisian patients was linked to chromosome 13q but the status of the 50DAG was not investigated. Here we show by linkage analysis of Algerian families that the genetic defect which leads, either directly or indirectly, to the deficiency of the 50DAG in skeletal muscle is localized to the proximal part of chromosome 13q. We have not found any evidence of genetic heterogeneity among the thirteen families studied. It remains to be demonstrated whether the 50DAG gene maps at 13q12, and to determine if it is mutated in this disease.
Hum Mol Genet 1993 Sep
PMID:Severe childhood autosomal recessive muscular dystrophy with the deficiency of the 50 kDa dystrophin-associated glycoprotein maps to chromosome 13q12. 824 65

Currently available techniques used to recognize point mutations in genetic disease are time consuming and are capable of screening only small pieces of DNA. Moreover, they detect all sequence differences including phenotypically silent changes. Consequently, they are not convenient to analyse mutations in large, multi-exonic genes, where a large fraction of pathological point mutations arises from early termination, as is the case for the one third non-deletion/duplication cases of Duchenne Muscular Dystrophy. We have developed a rapid and sensitive method, the Protein Truncation Test (PTT). PTT is based on a combination of RT-PCR, transcription and translation and selectively detects translation-terminating mutations. We demonstrate its effectiveness to detect point mutations in DMD-patients and carrier females. PTT should be widely applicable diagnostically in any disease where early terminations contribute substantially to the disease cause.
Hum Mol Genet 1993 Oct
PMID:Protein truncation test (PTT) for rapid detection of translation-terminating mutations. 826 29

Utrophin and dystrophin are highly homologous proteins which are reciprocally expressed in DMD (Duchenne muscular dystrophy) muscle. The remarkable similarity of these proteins suggests that they may play a similar cellular role in some circumstances; if this were the case then utrophin may be capable of replacing dystrophin in DMD patients. In this paper we show that the genomic structure of the utrophin gene is similar to the dystrophin gene, further exemplifying the relatedness of the two genes and their gene products. We have constructed a 1.25 Mb contig of eight yeast artificial chromosome (YAC) clones covering the utrophin gene located on chromosome 6q24. Utrophin is encoded by multiple small exons spanning approximately 900 kb. The distribution of exons within the genomic DNA has similarities to that of the dystrophin gene. In contrast to dystrophin, the utrophin gene has a long 5' untranslated region composed of two exons and a cluster of unmethylated, rare-cutting restriction enzyme sites at the 5' end of the gene. Similarities between the genomic structure suggest that utrophin and dystrophin arose through an ancient duplication event involving a large region of genomic DNA.
Hum Mol Genet 1993 Nov
PMID:The utrophin and dystrophin genes share similarities in genomic structure. 828 Nov 35

Duchenne and Becker muscular dystrophies (DMD/BMD) are caused by mutations in the human dystrophin gene. About two-thirds of DMD/BMD patients exhibit gross rearrangements in the gene whereas the mutations in the remaining one third are thought to be point mutations or minor structural lesions. By means of various progressive PCR-based techniques hitherto a number of point mutations has been described that in most cases should cause premature translational termination. These data indicate a particular functional importance for the C-terminal region of dystrophin and consequently for its gene products Dp 71 and Dp 116. To screen for microheterogeneities in this gene region we applied PCR-SSCP analysis to exons 60-79 of twenty-six DMD/BMD patients without detectable deletions. The study identified seven point mutations and one intron polymorphism. Six point mutations, found in DMD patients, should cause premature translational termination. One point mutation, identified in a BMD patient, results in an amino acid exchange. Five of the DMD patients bearing a point mutation are mentally retarded suggesting that a disruption of the translational reading frame in the C-terminal region is associated with this clinical finding in DMD cases. Therefore our data raise the possibility, that Dp 71 and/or Dp 116, the C-terminal translational products of dystrophin, may be causally involved in cases of mental retardation that are associated with DMD.
Hum Mol Genet 1993 Nov
PMID:Point mutations at the carboxy terminus of the human dystrophin gene: implications for an association with mental retardation in DMD patients. 828 Nov 50

The 70.8 kDa protein product of the distal part of the giant Duchenne muscular dystrophy (DMD) gene, Dp71, is expressed in many cell types and tissues. Anchored PCR, primer extension and functional analysis of transfected constructs were used to determine the 5' end of the mRNA and characterize the promoter of this major DMD gene product. The 5' untranslated region (5'UTR) of Dp71 is transcribed from a single exon; the promoter does not contain a TATA box, and has a very high GC content and several potential Sp1 binding sites. It is located more than 2000 kb 3' to the muscle and brain type dystrophin promoters and only 150 kb from the 3' end of the gene, suggesting that in most DMD patients the expression of Dp71 is unaffected.
Hum Mol Genet 1993 Nov
PMID:A housekeeping type promoter, located in the 3' region of the Duchenne muscular dystrophy gene, controls the expression of Dp71, a major product of the gene. 828 Nov 51

Duchenne-like muscular dystrophy (DLMD) is an autosomal recessive (AR) muscular dystrophy which presents a clinical course indistinguishable from the Xp21 Duchenne muscular dystrophy or DMD. Recently, Othmane et al., based on a linkage study with 13q12 markers in 3 highly inbred DLMD families from Tunisia, suggested that the gene for this myopathy lies in the pericentromeric region of chromosome 13q. It is unknown if there is genetic heterogeneity causing the DLMD phenotype. Therefore, the aim of the present report is to describe the results of linkage analysis in 4 Brazilian DLMD families with 13q12 markers (D13S115 and D13S120), which were also tested for 50DAG. It was possible to exclude the 13q gene at theta = 0.10 as responsible for the DLMD phenotype in our families using both 13q12 markers, if the lod scores of each family were added up. Interestingly, 3 families were deficient for 50 DAG while one showed a positive pattern for this glycoprotein. Therefore, these results suggest: a) the DLMD phenotype is caused by more than one recessive gene; b) a gene, not located at 13q, causes deficiency of 50 DAG as a primary or secondary defect.
Hum Mol Genet 1993 Nov
PMID:Genetic heterogeneity for Duchenne-like muscular dystrophy (DLMD) based on linkage and 50 DAG analysis. 828 Nov 58


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