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Rbfox1 downregulation and altered Calpain 3 splicing by FRG1 in a mouse model of facioscapulohumeral muscular dystrophy (FSHD).

ABSTRACT: FRG1 over-expression results in an FSHD-like phenotype in mice. Muscles (vastus lateralis and biceps brachii) from wild type and FRG1 over-expressing mice were compared at 4 and 13 weeks of age by splicing sensitive microarray.

ORGANISM(S): Mus musculus

PROVIDER: GSE32073 | GEO | 2012/12/01

SECONDARY ACCESSION(S): PRJNA147599

REPOSITORIES: GEO

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Rbfox1 downregulation and altered Calpain 3 splicing by FRG1 in a mouse model of facioscapulohumeral muscular dystrophy (FSHD).

Project description:FRG1 over-expression results in an FSHD-like phenotype in mice. Muscles (vastus lateralis and biceps brachii) from wild type and FRG1 over-expressing mice were compared at 4 and 13 weeks of age by splicing sensitive microarray. Comparisons at 4 different time points/muscles were performed between groups of 3 each FRG1 and WT mice.

2012-12-01 | E-GEOD-32073 | biostudies-arrayexpress

Expression profiling of FRG1 transgenic mice.

Project description:RNA from skeletal muscle of mice over-expressing selectively in the skeletal muscle the gene FRG1, a candidate of facioscapulohumeral muscular dystrophy, was compared to RNA from skeletal muscle of WT mice. Total RNA obtained from isolated vastus lateralis muscles of 4 weeks old females WT mice and vastus lateralis muscles of 4 weeks old mice over-expressing FRG1, FSHD region gene 1.

2013-09-04 | E-GEOD-28575 | biostudies-arrayexpress

Rbfox1 downregulation and altered calpain 3 splicing by FRG1 in a mouse model of Facioscapulohumeral muscular dystrophy (FSHD).

Project description:Facioscapulohumeral muscular dystrophy (FSHD) is a common muscle disease whose molecular pathogenesis remains largely unknown. Over-expression of FSHD region gene 1 (FRG1) in mice, frogs, and worms perturbs muscle development and causes FSHD-like phenotypes. FRG1 has been implicated in splicing, and we asked how splicing might be involved in FSHD by conducting a genome-wide analysis in FRG1 mice. We find that splicing perturbations parallel the responses of different muscles to FRG1 over-expression and disease progression. Interestingly, binding sites for the Rbfox family of splicing factors are over-represented in a subset of FRG1-affected splicing events. Rbfox1 knockdown, over-expression, and RNA-IP confirm that these are direct Rbfox1 targets. We find that FRG1 is associated to the Rbfox1 RNA and decreases its stability. Consistent with this, Rbfox1 expression is down-regulated in mice and cells over-expressing FRG1 as well as in FSHD patients. Among the genes affected is Calpain 3, which is mutated in limb girdle muscular dystrophy, a disease phenotypically similar to FSHD. In FRG1 mice and FSHD patients, the Calpain 3 isoform lacking exon 6 (Capn3 E6-) is increased. Finally, Rbfox1 knockdown and over-expression of Capn3 E6- inhibit muscle differentiation. Collectively, our results suggest that a component of FSHD pathogenesis may arise by over-expression of FRG1, reducing Rbfox1 levels and leading to aberrant expression of an altered Calpain 3 protein through dysregulated splicing.

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Effect of facioscapulohumeral dystrophy (FSHD) on skeletal muscle gene expression

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. Keywords: facioscapulohumeral dystrophy, skeletal muscle

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Transcriptional profiling in facioscapulohumeral muscular dystrophy to identify candidate biomarkers

Project description:Facioscapulohumeral muscular dystrophy (FSHD) is a progressive neuromuscular disorder caused by contractions of repetitive elements within the macrosatellite D4Z4 on chromosome 4q35. In order to develop mRNA-based biomarkers of affected muscles, we used GeneChip Gene 1.0 ST arrays for global analysis of gene expression in muscle biopsy specimens obtained from FSHD subjects and their unaffected first degree relatives. FSHD typically affects biceps muscles more severely than deltoid muscles. To examine muscle-specific expression changes associated with FSHD while controlling for background genetic variation, we analyzed RNA extracted from both biceps and deltoids of FSHD subjects and unaffected first-degree relatives.

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Gene expression profiles in muscle tissue from FSHD patients

2009-03-04 | GSE15090 | GEO

Transcription profiling of human Facioscapulohumeral muscular dystrophy (FSHD) muscle profiles

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

Gene expression profiles in muscle tissue from FSHD patients

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

FSHD region gene 1 (FRG1) is crucial for angiogenesis linking FRG1 to facioscapulohumeral muscular dystrophy-associated vasculopathy.

Project description:The genetic lesion that is diagnostic for facioscapulohumeral muscular dystrophy (FSHD) results in an epigenetic misregulation of gene expression, which ultimately leads to the disease pathology. FRG1 (FSHD region gene 1) is a leading candidate for a gene whose misexpression might lead to FSHD. Because FSHD pathology is most prominent in the musculature, most research and therapy efforts focus on muscle cells. Previously, using Xenopus development as a model, we showed that altering frg1 expression levels systemically leads to aberrant muscle development, illustrating the potential for aberrant FRG1 levels to disrupt the musculature. However, 50-75% of FSHD patients also exhibit retinal vasculopathy and FSHD muscles have increased levels of vascular- and endothelial-related FRG1 transcripts, illustrating an underlying vascular component to the disease. To date, no FSHD candidate gene has been proposed to affect the vasculature. Here, we focus on a role for FRG1 expression in the vasculature. We found that endogenous frg1 is expressed in both the developing and adult vasculature in Xenopus. Furthermore, expression of FRG1 was found to be essential for the development of the vasculature, as a knockdown of FRG1 resulted in decreased angiogenesis and reduced expression of the angiogenic regulator DAB2. Conversely, tadpoles subjected to frg1 overexpression displayed the pro-angiogenic phenotypes of increased blood vessel branching and dilation of blood vessels, and developed edemas, suggesting that their circulation was disrupted. Thus, the systemic upregulation of the FRG1 protein shows the potential for acquiring a disrupted vascular phenotype, providing the first link between a FSHD candidate gene and the vascular component of FSHD pathology. Overall, in conjunction with our previous analysis, we show that FRG1 overexpression is capable of disrupting both the musculature and vasculature, recapitulating the two most prominent features of FSHD.

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