calpain has been researched along with Muscular-Dystrophy--Facioscapulohumeral* in 4 studies
4 other study(ies) available for calpain and Muscular-Dystrophy--Facioscapulohumeral
Article | Year |
---|---|
Facioscapulohumeral muscular dystrophy and limb-girdle muscular dystrophy: "double trouble" overlapping syndrome?
Topics: Calpain; Chromosome Deletion; Chromosome Disorders; Chromosomes, Human, Pair 4; Female; Humans; Middle Aged; Muscle Proteins; Muscular Dystrophies, Limb-Girdle; Muscular Dystrophy, Facioscapulohumeral; Mutation; Phenotype; Syndrome | 2015 |
Rbfox1 downregulation and altered calpain 3 splicing by FRG1 in a mouse model of Facioscapulohumeral muscular dystrophy (FSHD).
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. Topics: Alternative Splicing; Animals; Calpain; Cells, Cultured; Disease Models, Animal; Exons; Gene Expression Regulation, Developmental; HEK293 Cells; Humans; Mice; Microfilament Proteins; Muscle Development; Muscle Proteins; Muscular Dystrophy, Facioscapulohumeral; Myoblasts; Proteins; RNA Splicing Factors; RNA-Binding Proteins | 2013 |
Patients with a phenotype consistent with facioscapulohumeral muscular dystrophy display genetic and epigenetic heterogeneity.
To identify the genetic and epigenetic defects in patients presenting with a facioscapulohumeral (FSHD) clinical phenotype without D4Z4 contractions on chromosome 4q35 tested by linear gel electrophoresis and Southern blot analysis.. The authors studied 16 patients displaying an FSHD-like phenotype, with normal cardiovascular and respiratory function, a myopathic pattern on electromyography, and a muscle biopsy being normal or displaying only mild and aspecific dystrophic changes. They sequenced the genes calpain 3 (CAPN3), valosin containing protein (VCP) and four-and-a-half LIM domains protein 1 (FHL1), and they analysed the D4Z4 repeat arrays by extensive genotyping and DNA methylation analysis.. The authors identified one patient carrying a complex rearrangement in the FSHD locus that masked the D4Z4 contraction associated with FSHD1 in standard genetic testing, one patient with somatic mosaicism for the D4Z4 4q35 contraction, six patients that were diagnosed as having FSHD2, four patients with CAPN3 mutations and two patients with a VCP mutation, No mutations were detected in FHL1, and in two patients, the authors could not identify the genetic defect.. In patients presenting with an FSHD-like clinical phenotype with a negative molecular testing for FSHD, consider (1) detailed genetic testing including D4Z4 contraction of permissive hybrid D4Z4 repeat arrays, p13E-11 probe deletions, and D4Z4 hypomethylation in the absence of repeat contraction as observed in FSHD2; (2) mutations in CAPN3 even in the absence of protein deficiency on western blot analysis; and (3) VCP mutations even in the absence of cognitive impairment, Paget disease and typical inclusion in muscle biopsy. Topics: Adenosine Triphosphatases; Adult; Calpain; Cell Cycle Proteins; DNA Mutational Analysis; Epigenesis, Genetic; Female; Genetic Association Studies; Humans; Intracellular Signaling Peptides and Proteins; LIM Domain Proteins; Male; Middle Aged; Mosaicism; Muscle Proteins; Muscular Dystrophy, Facioscapulohumeral; Phenotype; Valosin Containing Protein | 2012 |
Diagnosis by sequencing: correction of misdiagnosis from FSHD2 to LGMD2A by whole-exome analysis.
We studied and validated facioscapulohumeral muscular dystrophy (FSHD) samples from patients without a D4Z4 contraction (FSHD2 or 'phenotypic FSHD'). For this, we developed non-radioactive protocols to test D4Z4 allele constitution and DNA methylation, and applied these to samples from the Coriell Institute Cell Repository. The D4Z4 sizing showed two related subjects to have classic chromosome 4 contraction-dependent FSHD1. A third sample (GM17726) did not have a short chromosome 4 fragment, and had been assigned as non-4q FSHD (FSHD2). We tested D4Z4 haplotype and methylation for this individual but found both to be inconsistent with this diagnosis. Using exome sequencing, we identified two known pathogenic mutations in CAPN3 (Arg490Gln and Thr184Argfs(*)36), indicating a case of LGMD2A rather than FSHD. Our study shows how a wrong diagnosis can easily be corrected by whole-exome sequencing by constraining the variant analysis to candidate genes after the data have been generated. This new way of 'diagnosis by sequencing' is likely to become common place in genetic diagnostic laboratories. We also publish a digoxigenin-labeled Southern protocol to test D4Z4 methylation. Our data supports hypomethylation as a good epigenetic predictor for FSHD2. The non-radioactive protocol will help to make this assay more accessible to clinical diagnostic laboratories and the wider FSHD research community. Topics: Alleles; Base Sequence; Biological Assay; Calpain; Chromosomes, Human, Pair 4; Diagnosis, Differential; DNA Methylation; Epigenesis, Genetic; Exome; Female; Haplotypes; High-Throughput Nucleotide Sequencing; Humans; Male; Molecular Sequence Data; Muscle Proteins; Muscular Dystrophies, Limb-Girdle; Muscular Dystrophy, Facioscapulohumeral; Pedigree; Sequence Analysis, DNA; Sequence Deletion | 2012 |