Longitudinal measures of RNA expression and disease activity in FSHD muscle biopsies
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PROVIDER: PRJNA589062 | ENA |
REPOSITORIES: ENA
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Project description:Advances in understanding the pathophysiology of facioscapulohumeral dystrophy (FSHD) have led to the discovery of candidate therapeutics and it is important to identify markers of disease activity and progression to inform clinical trial design. For drugs that inhibit the expression of DUX4, measuring DUX4 or DUX4 target gene expression might be an interim outcome measure of drug activity, however, only a subset of muscle biopsies in FSHD show evidence of DUX4 expression. Our prior study showed that MRI T2-STIR positive muscles had a higher probability of showing DUX4 expression than muscles with normal MRI characteristics. In the current study, we performed a one-year follow-up assessment of the same muscle with repeat MRI and muscle biopsy. There was very little change in the muscle MRI characteristics over the one-year period and, similar to the initial evaluation MRI T2-STIR-postive muscles had a higher expression of DUX4 regulated genes, as well as genes associated with inflammation, extracellular matrix, and cell cycle. Compared to the initial evaluation, overall the level of expression in these gene categories remained stable over the one-year period, however, there was some variability for each individual muscle biopsied. We pooled the data from both the initial and one-year follow-up evaluations and identified several subgroups based on gene expression, as well as a set of genes that distinguished all of the FSHD samples from the controls that include DUX4-regulated genes, inflammatory immune genes, and cell cycle control genes. These candidate markers of disease activity need to be validated on independent datasets, but will hopefully be useful in studies of disease progression and response to therapy.
2020-02-25 | GSE140261 | GEO
Project description:Advances in understanding the pathophysiology of facioscapulohumeral dystrophy (FSHD) have led to the discovery of candidate therapeutics, and it is important to identify markers of disease activity to inform clinical trial design. For drugs that inhibit DUX4 expression, measuring DUX4 or DUX4-target gene expression might be an interim measure of drug activity; however, only a subset of FHSD muscle biopsies shows evidence of DUX4 expression. Our prior study showed that MRI T2-STIR-positive muscles had a higher probability of showing DUX4 expression than muscles with normal MRI characteristics. In the current study, we performed a 1-year follow-up assessment of the same muscle with repeat MRI and muscle biopsy. There was little change in MRI characteristics over the 1-year period and, similar to the initial evaluation, MRI T2-STIR-postive muscles had a higher expression of DUX4-regulated genes, as well as genes associated with inflammation, extracellular matrix and cell cycle. Compared to the initial evaluation, overall the level of expression in these gene categories remained stable over the 1-year period; however, there was some variability for each individual muscle biopsied. The pooled data from both the initial and 1-year follow-up evaluations identified several FSHD subgroups based on gene expression, as well as a set of genes-composed of DUX4-target genes, inflammatory and immune genes and cell cycle control genes-that distinguished all of the FSHD samples from the controls. These candidate markers of disease activity need to be replicated in independent datasets and, if validated, may provide useful measures of disease progression and response to therapy.
| S-EPMC7158378 | biostudies-literature
Project description:Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disorder linked to contractions of the D4Z4 repeat array in the subtelomeric region of chromosome 4q. By comparing genome-wide gene expression data from muscle biopsies of patients with FSHD to those of 11 other neuromuscular disorders, we intend to identify disease-specific changes which are more likely to be involved in the early stages of the disease progression. The data will help to identify pathological mechanisms involved in FSHD. Keywords: Differentiation design
2007-10-23 | GSE9397 | GEO
Project description:Muscle biopsies taken from vastus lateralis muscle of 30 normal subjects and 19 FSHD subjects (see PubMed ID 17151338); Affymetrix U133A and U133B arrays were scanned both before (S1) and after (S2) antibody enhancement. Effects of age and sex in normal subjects reported previously under GSE362, GSE674, and GSE9676. Experiment Overall Design: Gene expression profiles were generated for each individual for a total of 49 profiles (30 normal, 19 FSHD)
2008-04-06 | E-GEOD-10760 | biostudies-arrayexpress
Project description:Facioscapulohumeral muscular dystrophy (FSHD) is a common, dominantly inherited disease caused by the epigenetic de-repression of the DUX4 gene, a transcription factor normally repressed in somatic cells. As targeted therapies are now possible in FSHD, a better understanding of the relationship between DUX4 activity, muscle pathology and muscle MRI changes are crucial both to understand disease mechanisms and for the design of future clinical trials. Here, we performed MRIs of the lower extremities in 36 individuals with FSHD, followed by needle muscle biopsies in safely accessible muscles. We examined the correlation between MRI characteristics, muscle pathology, and expression of DUX4 target genes. Results show that the presence of elevated MRI STIR signal has substantial predictive value in identifying muscles with active disease and DUX4 target gene expression. In addition, DUX4 target gene expression was detected only in FSHD-affected muscles and not in control muscles, and higher levels of DUX4 target expression was associated with more advanced muscle pathology. These results support the use of MRI to identify FSHD muscles with active disease as measured by histopathology and DUX4 target gene expression and might be useful for the design of studies of disease progression and response to intervention.
2018-09-04 | GSE115650 | GEO
Project description:Muscle biopsies from biceps and deltoid were taken from 5 patients with FSHD, 5 asymptomatic carriers and 5 normal controls. The genome-wide expression patterns were compared using Affymetrix U133 Plus 2.0 chips. Keywords: Facioscapulohumeral, FSHD, muscular dystrophy
2009-03-04 | GSE15090 | GEO
Project description:Muscle biopsies from biceps and deltoid were taken from 5 patients with FSHD, 5 asymptomatic carriers and 5 normal controls. The genome-wide expression patterns were compared using Affymetrix U133 Plus 2.0 chips. Keywords: Facioscapulohumeral, FSHD, muscular dystrophy Gene expression profiles were generated for 15 individuals (5 affected patients, 5 asymptomatic carriers and 5 healthy controls)
2009-03-04 | E-GEOD-15090 | biostudies-arrayexpress
Project description:Facioscapulohumeral dystrophy (FSHD) is caused by decreased epigenetic repression of the D4Z4 macrosatellite array and recent studies have shown that this results in the expression of low levels of the DUX4 mRNA in skeletal muscle. Several other mechanisms have been suggested for FSHD pathophysiology and it remains unknown whether DUX4 expression can account for most of the molecular changes seen in FSHD. Since DUX4 is a transcription factor, we used RNA-seq to measure gene expression in muscle cells transduced with DUX4, and in muscle cells and biopsies from control and FSHD individuals. We show that DUX4 target gene expression is the major molecular signature in FSHD muscle together with a gene expression signature consistent with an immune cell infiltration. In addition, one unaffected individual without a known FSHD-causing mutation showed expression of DUX4 target genes. This individual has a sibling with FSHD and also without a known FSHD-causing mutation, suggesting the presence of yet unidentified modifier locus for DUX4 expression and FSHD. These findings demonstrate that expression of DUX4 accounts for the majority of the gene expression changes in FSHD skeletal muscle together with an immune cell infiltration. RNA-seq for muscle cells and biopsies from control and FSHD individuals.
2014-07-03 | E-GEOD-56787 | biostudies-arrayexpress
Project description:Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disorder linked to contractions of the D4Z4 repeat array in the subtelomeric region of chromosome 4q. By comparing genome-wide gene expression data from muscle biopsies of patients with FSHD to those of 11 other neuromuscular disorders, we intend to identify disease-specific changes which are more likely to be involved in the early stages of the disease progression. The data will help to identify pathological mechanisms involved in FSHD. Experiment Overall Design: Comparison of the profiles of FSHD to 13 other conditions for disease-specific changes. The 13 conditions are NHM (Normal healthy muscle) n=15; JDM (Juvenile dermatomyositis) n=25; HSP (Human spastic paraplegia) n=4; FSHD (facioscapulohumeral dystrophy) unaffected n=5, affected n=9; FKRP (Fukutin related protein deficiency) n=7; ED-L (Emery-Dreifuss muscular dystrophy, lamin A/C deficiency) n=4; ED-E (Emery-Dreifuss muscular dystrophy, emerin deficiency) n=4; DYSF (dysferlinopathy) n=10; DMD (Duchenne Muscular Dystrophy) n=10; CALP (Calpain-3 deficiency) n=10; BMD (Becker Muscular Dystrophy) n=5; AQM (Acute quadriplegic myopathy) n=5; ALS (Amyotrophic lateral sclerosis) n=9.
2008-06-16 | E-GEOD-9397 | biostudies-arrayexpress
Project description:RNAseq of FSHD and control LCLs and primary myoblasts with corresponding in vitro differentiated myotubes
2020-06-30 | GSE153523 | GEO