Gene expression profiling of Duchenne muscular dystrophy reveals characteristics along disease progression (original) (raw)
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Gene expression profiling of Duchenne muscular dystrophy skeletal muscle
2003
Abstract. The primary cause of Duchenne muscular dystrophy (DMD) is a mutation in the dystrophin gene, leading to absence of the corresponding protein, disruption of the dystrophin-associated protein complex, and substantial changes in skeletal muscle pathology. Although the primary defect is known and the histological pathology well documented, the underlying molecular pathways remain in question.
cDNA microarray analysis of individual Duchenne muscular dystrophy patients
Human Molecular Genetics, 2003
We have developed a novel cDNA microarray encompassing 3500 genes expressed in skeletal muscle. With this system, we have performed the first study of gene expression in samples from individual patients. We analyzed muscle specimen from individuals with Duchenne muscular dystrophy to identify differences among patients. Among the variably expressed genes, we focused on the expression of the genes encoding HLA-related proteins, myosin light chains and troponin Ts as markers of muscle necrosis and regeneration. The expression patterns of these genes correlated with the severity of dystrophic changes on histological examination. Our cDNA microarray provides a new tool to investigate molecular muscle pathology.
Proceedings of the National Academy of Sciences of the United States of America, 2002
The primary cause of Duchenne muscular dystrophy (DMD) is a mutation in the dystrophin gene leading to the absence of the corresponding RNA transcript and protein. Absence of dystrophin leads to disruption of the dystrophin-associated protein complex and substantial changes in skeletal muscle pathology. Although the histological pathology of dystrophic tissue has been well documented, the underlying molecular pathways remain poorly understood. To examine the pathogenic pathways and identify new or modifying factors involved in muscular dystrophy, expression microarrays were used to compare individual gene expression profiles of skeletal muscle biopsies from 12 DMD patients and 12 unaffected control patients. Two separate statistical analysis methods were used to interpret the resulting data: t test analysis to determine the statistical significance of differential expression and geometric fold change analysis to determine the extent of differential expression. These analyses identif...
Neuromuscular Disorders, 2001
Mutations in the dystrophin gene lead to dystrophin de®ciency, which is the cause of Duchenne muscular dystrophy (DMD). This important discovery more than 10 years ago opened a new ®eld for very productive investigations. However, the exact functions of dystrophin are still not fully understood and the complex process leading to subsequent muscle ®ber necrosis has not been clearly described; hence there has not yet been any marked improvement in patient treatment. To decipher the molecular mechanisms induced by a lack of dystrophin, we started identifying genes whose expression is altered in DMD skeletal muscles. The approach was based on differential screening of a human muscle cDNA array. Nine genes were found to be up-or downregulated. Our results indicate expression alterations in mitochondrial genes, titin, a muscle transcription factor and three novel genes. First characterizations of these novel genes indicated that two of them have striated muscle tissue speci®city.
Altered Gene Expression Pathways in Duchenne Muscular Dystrophy
2012
Ca 2+ is a highly versatile second messenger that can regulate several cellular functions. Skeletal muscles use Ca 2+ for contraction process and as regulatory signaling molecule. Subsequently, muscle plasticity is closely related with calcium signals .
PLOS Computational Biology, 2012
Elucidation of new biomarkers and potential drug targets from high-throughput profiling data is a challenging task due to a limited number of available biological samples and questionable reproducibility of differential changes in cross-dataset comparisons. In this paper we propose a novel computational approach for drug and biomarkers discovery using comprehensive analysis of multiple expression profiling datasets. The new method relies on aggregation of individual profiling experiments combined with leave-one-dataset-out validation approach. Aggregated datasets were studied using Sub-Network Enrichment Analysis algorithm (SNEA) to find consistent statistically significant key regulators within the global literature-extracted expression regulation network. These regulators were linked to the consistent differentially expressed genes. We have applied our approach to several publicly available human muscle gene expression profiling datasets related to Duchenne muscular dystrophy (DMD). In order to detect both enhanced and repressed processes we considered up-and down-regulated genes separately. Applying the proposed approach to the regulators search we discovered the disturbance in the activity of several muscle-related transcription factors (e.g. MYOG and MYOD1), regulators of inflammation, regeneration, and fibrosis. Almost all SNEA-derived regulators of down-regulated genes (e.g. AMPK, TORC2, PPARGC1A) correspond to a single common pathway important for fast-to-slow twitch fiber type transition. We hypothesize that this process can affect the severity of DMD symptoms, making corresponding regulators and downstream genes valuable candidates for being potential drug targets and exploratory biomarkers.
Expression Profiling In the Muscular Dystrophies
The Journal of Cell …, 2000
We used expression profiling to define the pathophysiological cascades involved in the progression of two muscular dystrophies with known primary biochemical defects, dystrophin deficiency (Duchenne muscular dystrophy) and ␣ -sarcoglycan deficiency (a dystrophin-associated protein). We employed a novel protocol for expression profiling in human tissues using mixed samples of multiple patients and iterative comparisons of duplicate datasets. We found evidence for both incomplete differentiation of patient muscle, and for dedifferentiation of myofibers to alternative lineages with advancing age. One developmentally regulated gene characterized in detail, ␣ -cardiac actin, showed abnormal persistent expression after birth in 60% of Duchenne dystrophy myofibers. The majority of myofibers ( ف 80%) remained strongly positive for this protein throughout the course of the disease. Other developmentally regulated genes that showed widespread overexpression in these muscular dystrophies included embryonic myosin heavy chain, versican, acetylcholine receptor ␣ -1, secreted protein, acidic and rich in cysteine/osteonectin, and thrombospondin 4. We hypothesize that the abnormal Ca 2 ϩ influx in dystrophin-and ␣ -sarcoglycan-deficient myofibers leads to altered developmental programming of developing and regenerating myofibers. The finding of upregulation of HLA-DR and factor XIIIa led to the novel identification of activated dendritic cell infiltration in dystrophic muscle; these cells mediate immune responses and likely induce microenvironmental changes in muscle. We also document a general metabolic crisis in dystrophic muscle, with large scale downregulation of nuclear-encoded mitochondrial gene expression. Finally, our expression profiling results show that primary genetic defects can be identified by a reduction in the corresponding RNA.
PloS one, 2018
Although the genetic basis of Duchenne muscular dystrophy has been known for almost thirty years, the cellular and molecular mechanisms characterizing the disease are not completely understood and an efficacious treatment remains to be developed. In this study we analyzed proteomics data obtained with the SomaLogic technology from blood serum of a cohort of patients and matched healthy subjects. We developed a workflow based on biomarker identification and network-based pathway analysis that allowed us to describe different deregulated pathways. In addition to muscle-related functions, we identified other biological processes such as apoptosis, signaling in the immune system and neurotrophin signaling as significantly modulated in patients compared with controls. Moreover, our network-based analysis identified the involvement of FoxO transcription factors as putative regulators of different pathways. On the whole, this study provided a global view of the molecular processes involved...
The FASEB Journal, 2007
Genome-wide gene expression profiling of skeletal muscle from Duchenne muscular dystrophy (DMD) patients has been used to describe muscle tissue alterations in DMD children older than 5 years. By studying the expression profile of 19 patients younger than 2 years, we describe with high resolution the gene expression signature that characterizes DMD muscle during the initial or "presymptomatic" phase of the disease. We show that in the first 2 years of the disease, DMD muscle is already set to express a distinctive gene expression pattern considerably different from the one expressed by normal, age-matched muscle. This "dystrophic" molecular signature is characterized by a coordinate induction of genes involved in the inflammatory response, extracellular matrix (ECM) remodeling and muscle regeneration, and the reduced transcription of those involved in energy metabolism. Despite the lower degree of muscle dysfunction experienced, our younger patients showed abnormal expression of most of the genes reported as differentially expressed in more advanced stages of the disease. By analyzing our patients as a time series, we provide evidence that some genes, including members of three pathways involved in morphogenetic signaling-Wnt, Notch, and BMPare progressively induced or repressed in the natural history of DMDexpression profiling in the early phases of DMD: a constant molecular signature characterizes DMD muscle from early postnatal life throughout disease progression. FASEB J. 21, 1210 -1226
Molecular & Cellular Proteomics, 2020
The absence of the dystrophin protein in Duchenne muscular dystrophy (DMD) results in myofiber fragility and a plethora of downstream secondary pathologies. While a variety of experimental therapies are in development, achieving effective treatments for DMD remains exceptionally challenging, not least because the pathological consequences of dystrophin loss are incompletely understood. Here we have performed proteome profiling in tibialis anterior muscles from two murine DMD models (mdx and mdx52) at three ages (8, 16, and 80 weeks of age), all n=3. High-resolution isoelectric focusing liquid chromatography-tandem mass spectrometry (HiRIEF-LC-MS/MS) was used to quantify the expression of 4,974 proteins across all 27 samples. The two dystrophic models were found to be highly similar, whereas multiple proteins were differentially expressed relative to wild-type (C57BL/6) controls at each age. Furthermore, 1,795 proteins were differentially expressed when samples were pooled across age...