1,721,975 research outputs found
The 5' region of intron 11 of the dystrophin gene contains target sequences for mobile elements and three overlapping ORFs
No full textWe have characterised the 2371 bp 5' end of intron 11 of the dystrophin gene. Comparative analysis of this intronic region revealed homologies with the following sequences: regions containing mobile elements; target sites for numerous transcription factors, two resolvases, and a histone-like DNA binding protein; three eukaryotic promoters. In addition, we identified three partially overlapping ORFs, and transcription analysis confirmed that one of these is expressed, representing the first gene reported to overlap the human dystrophin gene. We have also characterised a 136 bp sequence rearranged in intron 11 in a patient affected by X-linked dilated cardiomyopathy due to a dystrophinopathy. This is a multiple copy sequence with features of a repetitive element. Its comparative analysis showed a very high homology with human genomic and EST regions, adjacent and clustered with Alu, LINE1, and THE elements. The pattern of homology suggests that it may represent a novel Alu-like, transcriptionally active sequence with a possible retrotransposable capacity. We hypothesise that the 5' region of the dystrophin intron 11, containing common target areas for the insertion of mobile elements, may have a role in the rearrangement of this novel Alu-like sequence
Dystrophin and mutations: One gene, several proteins, multiple phenotypes
No full textA large and complex gene on the X chromosome encodes
dystrophin. Many mutations have been described in this
gene, most of which affect the expression of the muscle
isoform, the best-known protein product of this locus. These
mutations result in the Duchenne and Becker muscular
dystrophies (DMD and BMD). However, there are several
other tissue specific isoforms of dystrophin, some
exclusively or predominantly expressed in the brain or the
retina. Mutations affecting the correct expression of these
tissue-specific isoforms have been associated with the CNS
involvement common in DMD. Rare mutations also account
for the allelic disorder X-linked dilated cardiomyopathy, in
which dystrophin expression or function is affected mostly
or exclusively in the heart. Genotype definition of the
dystrophin gene in patients with dystrophinopathies has
taught us much about functionally important domains of the
protein itself and has provided insights into several
regulatory mechanisms governing the gene expression
profile. Here, we focus on current understanding of the
genotype–phenotype relation for mutations in the dystrophin
gene and their implications for gene functions
Deletion of distrophin muscle promoter region associated with X-linked dilated cardiomyopathy
No full textRevertant fibres and dystrophin traces in Duchenne muscular dystrophy: Implication for clinical trials
No full textDuchenne muscular dystrophy (DMD) is characterised by the absence of dystrophin in muscle biopsies, although residual dystrophin can be present, either as dystrophin-positive (revertant) fibres or traces. As restoration of dystrophin expression is the end point of clinical trials, such residual dystrophin is a key factor in recruitment of patients and may also confound the analysis of dystrophin restoration in treated patients, if, as previously observed in the mdx mouse, revertant fibres increase with age. In 62% of the diagnostic biopsies reports of 65 DMD patients studied, traces or revertants were recorded with no correlation between traces or revertants, the patients' performance, or corticosteroids response. In nine of these patients, there was no increase in traces or revertants in biopsies taken a mean of 8.23 years (5.8-10.4 years) after the original diagnostic biopsy. This information should help in the design and execution of clinical trials focused on dystrophin restoration strategies. (C) 2010 Elsevier B.V. All rights reserved
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
In vivo study of an aberrant dystrophin exon inclusion in X-linked dilated cardiomyopathy
No full textWe previously identified a dystrophin intron 11 rearrangement in one family with X-linked dilated cardiomyopathy, causing incorporation of an aberrant exon in a tissue-specific manner. In this study we analyzed the role of different intron 11 genomic regions in the regulation of splicing by using mini-genes based approach, in C2C12 (skeletal muscle) myoblasts and myotubes, H9C2 cardiomyocytes, and HeLa cells. We show that inclusion of the aberrant exon is favored in H9C2 and differentiated C2C12 myotubes. These data suggest that the aberrant exon undergoes a differentiation-specific splicing. Unexpectedly, length of intron has a favorable effect in inclusion of the aberrant exon in the cardiac cells, suggesting that cardiac cells might be more prone to steric hindrance of trans-acting factors, involved in the inclusion of the aberrant exon. Furthermore, the cultured cell system used can serve as a suitable model to study human alternative splicing
Congenital muscle disorders with cores: the ryanodine receptor calcium channel paradigm
No full textDysregulation of calcium signals due to defects of skeletal muscle sarcoplasmic reticulum calcium release channel (ryanodine receptor; RyR1) is causative of several congenital muscle disorders including malignant hyperthermia (MH; MIM #145600), Central Core Disease (CCD; MIM #11700), Multiminicore Disease (MmD; MIM # 255320) and Centronuclear myopathy (CNM). Experimental data have show that RYR1 mutations result mainly in four types of channel defects. One class of RYR1 mutations (MH) cause the channels to become hypersensitive to activation by electrical and pharmacological stimuli. The second class of RYR1 mutations (CCD) result in leaky channels leading to a depletion of Ca2+ from the SR store. A third class of RYR1 mutations linked to CCD causes excitation-contraction uncoupling, whereby activation of the voltage sensor Cav1.1 is unable to release calcium from the SR store. The forth class of mutations are unveiled by wild type allele silencing, and cause a decrease of mutant RyR1 channels to be expressed in SR membranes. In this review, we discuss the classes of RYR1 mutations which have been associated with CCD, MmD and related neuromuscular phenotypes
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