Project description:HIBM is a neuromuscular disorder characterized by adult-onset, slowly progressive distal and proximal muscle weakness. Here, gene expression was measured in muscle specimens from 10 HIBM patients carrying the M712T Persian Jewish founder mutation in GNE and presenting with mild histological changes, and from 10 healthy matched control individuals. Keywords: Muscle specimen
2008-09-04 | GSE12648 | GEO
Project description:Case report: Novel genetic variant associated with epilepsy
Project description:Caveolins are structural and functional proteins in plasma membrane invaginations called caveolae. Mutations in Caveolin-3 cause myopathies of variable severity. The pathogenicity of the Caveolin-3 variant G55S is still unclear. Here, we report on three patients suffering from mild to moderate myopathy. In all three patients, but also in two seemingly unaffected family members of patient one the G55S variant was found. Histology revealed moderate chronic myopathic changes and reduced sarcolemmal Caveolin-3 immunoreactivity in all three cases. Immunoblots for Caveolin-3 were abnormal in all cases. By electron microscopy, enlarged caveolae were detected in case one and three and vacuolar myopathy in case two. EM studies of RCMH myoblasts transfected with G55S Caveolin-3 revealed autophagic vacuoles. The alterations in Golgi morphology were in line with pathological Caveolin-3 deposits in this organelle detected by immunofluorescence and indicative for activation of autophagy. Phospho-blotting demonstrated that G55S affects EGFR signaling. Proteomic profiling of transfected RCMH myoblasts demonstrated alterations in levels of physiologically relevant proteins which are indicative for antagonization of G55S Caveolin-3 expression. Some proteomic alterations were enhanced by osmotic/mechanical stress. In conclusion, our results suggest that the G55S Caveolin-3 sequence variant can be compensated by cellular defense mechanisms and that additional stress may lead to vulnerability of G55S Caveolin-3 expressing muscle cells.
Project description:HIBM is a neuromuscular disorder characterized by adult-onset, slowly progressive distal and proximal muscle weakness. Here, gene expression was measured in muscle specimens from 10 HIBM patients carrying the M712T Persian Jewish founder mutation in GNE and presenting with mild histological changes, and from 10 healthy matched control individuals. Experiment Overall Design: Samples were taken from muscle specimens (deltoid, biceps, quadriceps, tibialis), from 10 HIBM patients carrying the M712T Persian Jewish founder mutation in GNE and presenting with mild histological changes. Ages of patients range between 20 to 59. Additional 10 matched samples were taken from healthy control individuals (deltoid, biceps, quadriceps, gluteus, paraspinally and triceps muscles), with age range 18 to 74.
Project description:Tibial muscular dystrophy (TMD) is a late onset, autosomal dominant distal myopathy that results from mutations in the two last domains of titin. The cascade of molecular events leading from the causative Titin mutations to the preterm death of muscle cells in TMD is largely unknown. To identify these components, we used gene expression profiling of muscle biopsies from TMD patients and healthy controls. 5 muscle samples from 2 normal control subjects and muscle samples from 7 TMD subjects.
Project description:The SLC25A26 gene encodes a mitochondrial inner membrane carrier that transports S-adenosylmethionine (SAM) into the mitochondrial matrix in exchange for S-adenosylhomocysteine (SAH). SAM is the predominant methyl-group donor for most cellular methylation processes, of which SAH is produced as a by-product. Pathogenic, bi-allelic SLC25A26 variants are a recognized cause of mitochondrial disease in children, with a severe neonatal-onset caused by decreased SAM transport activity. We describe two, unrelated adult cases presenting with exercise intolerance and mitochondrial myopathy associated with bi-allelic variants in SLC25A26 which lead to marked respiratory chain deficiencies and mitochondrial histopathological abnormalities in skeletal muscle that are comparable to the early-onset cases. We demonstrate using both mouse and fruit fly models that impairment of SAH, rather than SAM, transport across the mitochondrial membrane is the cause of this milder, later onset clinical phenotype. In this submission, the total larval proteome was assessed at two, three and four days after egg laying in mutants expressing a SAMC.R166Q mutation versus wDah genetic background controls. Our finding of a novel pathomechanism associated with a known disease-causing protein highlights the potential of precision medicine in clinical decision making.
