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Project description:ObjectiveTo define the transcriptomic changes responsible for the histologic alterations in skeletal muscle and their progression in collagen VI-related muscular dystrophy (COL6-RD).MethodsCOL6-RD patient muscle biopsies were stratified into three groups based on the overall level of pathologic severity considering degrees of fibrosis, muscle fiber atrophy, and fatty replacement of muscle tissue. Using microarray and RNA-Seq, we then performed global gene expression profiling on the same muscle biopsies and compared their transcriptome with age- and sex-matched controls.ResultsCOL6-RD muscle biopsy transcriptomes as a group revealed prominent upregulation of muscle extracellular matrix component genes and the downregulation of skeletal muscle and mitochondrion-specific genes. Upregulation of the TGFβ pathway was the most conspicuous change across all biopsies and was fully evident even in the mildest/earliest histological group. There was no difference in the overall transcriptional signature between the different histologic groups but polyserial analysis identified relative changes along with COL6-RD histological severity.InterpretationOverall, our study establishes the prominent dysregulation of extracellular matrix genes, TGFβ signaling, and its downstream cellular pathways at the transcriptomic level in COL6-RD muscle.
| S-EPMC8607456 | biostudies-literature
Project description:Collagen VI-related muscular dystrophies (COL6RD) are a rare, inherited group of congenital muscular dystrophies. The phenotype spans from an early-onset, severe, and rapidly progressive clinical course in Ullrich congenital muscular dystrophy (UCMD), to a late-onset, mild and slowly progressive form in Bethlem muscular dystrophy (BM). COL6RD are caused by pathogenic variants in any of the three collagen type VI genes (COL6A1, COL6A2, COL6A3), which cause absence, reduction, mislocalization, or dysfunction of the collagen VI microfibrils in the skeletal muscle extracellular matrix (myomatrix), leading to yet incompletely understood downstream effects. Pathologic alterations in muscle biopsies of COL6RD varies, ranging from severely dystrophic changes, to mildly myopathic, represented by isolated myofiber atrophy. In this study, we aim to define the pathophysiologic events responsible for the histologic alterations of muscle and their progression in COL6RD. Aided by automated image analysis, we reviewed COL6RD patient muscle biopsies (n=22) and stratified them to three groups based on the degree of fibrosis and muscle fiber atrophy. Using microarray and RNA-Seq, we then performed global gene expression profiling on the same muscle biopsies and compared it with controls (n=14). Different histologic groups were characterized by similar transcriptional signatures predominantly featuring the upregulation of myomatrix component genes and downregulation of skeletal muscle and mitochondrion-specific genes. Our results also identified the TGFβ1 pathway in strong correlation with the development of COL6RD pathology at the histologic level, beginning early in the disease process, preceding fibrosis, and increasing in direct correlation with increased histologic severity. Overall, our study identifies COL6RD as a primary disorder of the myomatrix and posits dysregulation of TGFβ1-dependent pathways as a potential factor in pathogenesis of the disease.
2022-03-22 | GSE103972 | GEO
Project description:Collagen VI-related muscular dystrophies (COL6RD) are a rare, inherited group of congenital muscular dystrophies. The phenotype spans from an early-onset, severe, and rapidly progressive clinical course in Ullrich congenital muscular dystrophy (UCMD), to a late-onset, mild and slowly progressive form in Bethlem muscular dystrophy (BM). COL6RD are caused by pathogenic variants in any of the three collagen type VI genes (COL6A1, COL6A2, COL6A3), which cause absence, reduction, mislocalization, or dysfunction of the collagen VI microfibrils in the skeletal muscle extracellular matrix (myomatrix), leading to yet incompletely understood downstream effects. Pathologic alterations in muscle biopsies of COL6RD varies, ranging from severely dystrophic changes, to mildly myopathic, represented by isolated myofiber atrophy. In this study, we aim to define the pathophysiologic events responsible for the histologic alterations of muscle and their progression in COL6RD. Aided by automated image analysis, we reviewed COL6RD patient muscle biopsies (n=22) and stratified them to three groups based on the degree of fibrosis and muscle fiber atrophy. Using microarray and RNA-Seq, we then performed global gene expression profiling on the same muscle biopsies and compared it with controls (n=14). Different histologic groups were characterized by similar transcriptional signatures predominantly featuring the upregulation of myomatrix component genes and downregulation of skeletal muscle and mitochondrion-specific genes. Our results also identified the TGFβ1 pathway in strong correlation with the development of COL6RD pathology at the histologic level, beginning early in the disease process, preceding fibrosis, and increasing in direct correlation with increased histologic severity. Overall, our study identifies COL6RD as a primary disorder of the myomatrix and posits dysregulation of TGFβ1-dependent pathways as a potential factor in pathogenesis of the disease.
2022-03-22 | GSE103608 | GEO
Project description:Transcriptome analysis of collagen VI-related muscular dystrophy muscle biopsies
| PRJNA407811 | ENA
Project description:Transcriptome analysis of collagen VI-related muscular dystrophy muscle biopsies [Microarray].
| PRJNA407810 | ENA
Project description:The collagen VI related muscular dystrophies (COL6-RD), Ullrich congenital muscular dystrophy (UCMD) and Bethlem myopathy (BM) are among the most common congenital muscular dystrophies and are characterized by distal joint laxity and a combination of distal and proximal joint contractures. Inheritance can be dominant negative (DN) or recessive depending on the type and location of the mutation. DN mutations allow incorporation of abnormal chains into secreted tetramers and are the most commonly identified mutation type in COL6-RD. Null alleles (nonsense, frameshift, and large deletions) do not allow incorporation of abnormal chains and act recessively. To better define the pathways disrupted by mutations in collagen VI, we have used a transcriptional profiling approach with RNA-Seq to identify differentially expressed genes in COL6-RD individuals from controls.RNA-Seq allows precise detection of all expressed transcripts in a sample and provides a tool for quantification of expression data on a genomic scale. We have used RNA-Seq to identify differentially expressed genes in cultured dermal fibroblasts from 13 COL6-RD individuals (8 dominant negative and 5 null) and 6 controls. To better assess the transcriptional changes induced by abnormal collagen VI in the extracellular matrix (ECM); we compared transcriptional profiles from subjects with DN mutations and subjects with null mutations to transcriptional profiles from controls.Differentially expressed transcripts between COL6-RD and control fibroblasts include upregulation of ECM components and downregulation of factors controlling matrix remodeling and repair. DN and null samples are differentiated by downregulation of genes involved with DNA replication and repair in null samples.Differentially expressed genes identified here may help identify new targets for development of therapies and biomarkers to assess the efficacy of treatments.
| S-EPMC5731705 | biostudies-literature
Project description:Mutations in the genes COL6A1, COL6A2, and COL6A3, coding for three ? chains of collagen type VI, underlie a spectrum of myopathies, ranging from the severe congenital muscular dystrophy-type Ullrich (UCMD) to the milder Bethlem myopathy (BM), with disease manifestations of intermediate severity in between. UCMD is characterized by early-onset weakness, associated with pronounced distal joint hyperlaxity and the early onset or early progression of more proximal contractures. In the most severe cases ambulation is not achieved, or it may be achieved only for a limited period of time. BM may be of early or later onset, but is milder in its manifestations, typically allowing for ambulation well into adulthood, whereas typical joint contractures are frequently prominent. A genetic spectrum is emerging, with BM being caused mostly by dominantly acting mutations, although rarely recessive inheritance of BM is also possible, whereas both dominantly as well as recessively acting mutations underlie UCMD.
| S-EPMC5207779 | biostudies-literature
Project description:Objectives: The collagen VI related muscular dystrophies (COL6-RD), Ullrich congenital muscular dystrophy (UCMD) and Bethlem myopathy (BM) are among the most common congenital muscular dystrophies, but the pathogenesis, including the role of mutant collagen VI in the matrix is poorly understood. To better define the pathways disrupted by mutations in collagen VI, we have used a transcriptional profiling approach with RNA-Seq to identify differentially expressed genes in COL6-RD patients from controls. Methods: We have used RNA-Seq to identify differentially expressed genes in cultured dermal fibroblasts from 13 COL6-RD patients (8 dominant negative and 5 null) and 6 controls. Sequence reads were analyzed using the TopHat/Cufflinks pipeline. Results: Differentially expressed transcripts between COL6-RD patient and control fibroblasts include upregulation of ECM components and downregulation of factors controlling matrix remodeling and repair. DN and null samples are differentiated by downregulation of genes involved with DNA replication and repair in null samples
2017-12-04 | GSE103270 | GEO
Project description:Laminin ?2 deficient congenital muscular dystrophy, caused by mutations in the LAMA2 gene, is characterized by early muscle weakness associated with abnormal white matter signal on cerebral MRI.To report on 4 patients with LAMA2 gene mutations whose original clinical features complicated the diagnosis strategy.Clinical, electrophysiological, muscle imaging and histopathological data were retrospectively collected from all patients. DNA samples were analysed by next-generation sequencing or direct gene sequencing. Laminin ?2 was analysed by western-blot and immunohistochemistry.The four patients achieved independent walking. All had proximal muscle weakness with scapular winging and prominent joint contractures without peripheral neuropathy. During follow-up, two patients suffered from refractory epilepsy associated with brain leukoencephalopathy in one, polymicrogyria and lissencephaly without white matter changes in the other. In two patients, the distribution of fatty infiltration resembles that of collagen-VI related myopathies. Dilated cardiomyopathy contstartabstractwith conduction defects, suggestive of Emery-Dreifuss myopathy, emerged in two of them within the 4th decade. Molecular diagnosis remained elusive for many years. Finally, targeted capture-DNA sequencing unveiled the involvement of the LAMA2 gene in two families, and led us to further identify LAMA2 mutations in the remaining family using Sanger sequencing.This report extends the clinical and radiological features of partial Laminin ?2 deficiency since patients showed atypical manifestations including dilated cardiomyopathy with conduction defects in 2, epilepsy in 2, one of whom also had sole cortical brain abnormalities. Importantly, clinical findings and muscle imaging initially pointed to collagen-VI related disorders and Emery-Dreifuss muscular dystrophy.
| S-EPMC5240538 | biostudies-literature
Project description:BackgroundMesenchymal stromal cells (MSCs) function as supportive cells on skeletal muscle homeostasis through several secretory factors including type 6 collagen (COL6). Several mutations of COL6A1, 2, and 3 genes cause Ullrich congenital muscular dystrophy (UCMD). Skeletal muscle regeneration deficiency has been reported as a characteristic phenotype in muscle biopsy samples of human UCMD patients and UCMD model mice. However, little is known about the COL6-dependent mechanism for the occurrence and progression of the deficiency. The purpose of this study was to clarify the pathological mechanism of UCMD by supplementing COL6 through cell transplantation.MethodsTo test whether COL6 supplementation has a therapeutic effect for UCMD, in vivo and in vitro experiments were conducted using four types of MSCs: (1) healthy donors derived-primary MSCs (pMSCs), (2) MSCs derived from healthy donor induced pluripotent stem cell (iMSCs), (3) COL6-knockout iMSCs (COL6KO-iMSCs), and (4) UCMD patient-derived iMSCs (UCMD-iMSCs).ResultsAll four MSC types could engraft for at least 12 weeks when transplanted into the tibialis anterior muscles of immunodeficient UCMD model (Col6a1KO) mice. COL6 protein was restored by the MSC transplantation if the MSCs were not COL6-deficient (types 1 and 2). Moreover, muscle regeneration and maturation in Col6a1KO mice were promoted with the transplantation of the COL6-producing MSCs only in the region supplemented with COL6. Skeletal muscle satellite cells derived from UCMD model mice (Col6a1KO-MuSCs) co-cultured with type 1 or 2 MSCs showed improved proliferation, differentiation, and maturation, whereas those co-cultured with type 3 or 4 MSCs did not.ConclusionsThese findings indicate that COL6 supplementation improves muscle regeneration and maturation in UCMD model mice.
| S-EPMC8351132 | biostudies-literature