Sarcospan selectively interfaces with sarcoglycan subunits to stabilize the sarcolemma and prevent limb-girdle muscular dystrophy
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1233349 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Gene duplication events provide redundancy to complex organisms, and homologous genes and their encoded proteins are potential replacements to treat loss-of-function genetic syndromes. Skeletal muscle possesses redundant molecular mechanisms that partially or fully compensate for loss of gene function. Within the dystrophin-glycoprotein complex (DGC), utrophin is known to substitute for dystrophin. However, there has been little investigation of the orthologous relationships within the sarcoglycan subcomplex of the DGC. In skeletal muscle, the sarcoglycan complex canonically consists of alpha-, beta-, gamma- and delta-subunits, with gamma- and delta-sarcoglycan showing the greatest homology but no functional redundancy. We show that sarcospan, a transmembrane scaffolding protein, mediates assembly of a compensatory DGC with gamma-sarcoglycan replacement by zeta-sarcoglycan. This alternative complex improved pathology ingamma-sarcoglycan muscular dystrophy, but not alpha- or beta-sarcoglycan muscular dystrophy where sarcospan was unable to form compensatory complexes. Three-dimensional modeling of the compensatory DGC reveals that zeta-sarcoglycan maintains specific hydrophobic interactions with sarcospan and preserves overall quaternary arrangement. This compensatory DGC protects the cell membrane from contraction-induced damage and all secondary consequences of disease. These findings demonstrate a novel mechanism stabilizing the DGC by leveraging protein redundancy, with an important role for sarcospan in assembly and scaffolding of a compensatory DGC.
2025-06-01 | GSE291423 | GEO
Project description:26 limb-girdle muscular dystrophy patients from Latvia and 34 patients from Lithuania with clinical symptoms of limb-girdle muscular dystrophies, along with 204 healthy unrelated controls were genotyped for 96 most frequent known limb-girdle muscular dystrophies causing mutations for the region, using VeraCode GoldenGate system. More information can be found in article Robust genotyping tool for autosomal recessive type of limb-girdle muscular dystrophies in BMC Musculoskeletal Disorders by I. Inashkina et al.
2016-04-28 | E-MTAB-4662 | biostudies-arrayexpress
Project description:Mesoangioblasts are stem/progenitor cells derived from a subset of pericytes expressing alkaline phosphatase. They have been shown to ameliorate muscular dystrophies (currently incurable diseases) in different animal models and are now undergoing clinical experimentation for Duchenne muscular dystrophy. We show here that patients affected by limb-girdle muscular dystrophy 2D (LGMD2D, characterized by M-NM-1-sarcoglycan deficit) have a reduction of this subset of pericytes and hence mesoangioblast could not be derived for cell therapy. Therefore, we reprogrammed LGMD2D fibroblasts and myoblasts to induced pluripotent stem cells (iPSCs) and developed a protocol for the derivation of mesoangioblast-like cells from them. These cells can be expanded and genetically corrected with a muscle-specific lentiviral vector expressing human M-NM-1-sarcoglycan. Upon transplantation into ad hoc generated M-NM-1-sarcoglycan-null immunodeficient mice, they generate myofibers expressing M-NM-1-sarcoglycan. This approach may be useful for muscular dystrophies that show a reduction of resident progenitors and provides evidence of pre-clinical safety and efficacy of disease-specific iPSCs. 9 samples analyzed: 3 WT HIDEMs, 3 Limb-girdle muscular dystrophy 2D (LGMD2D) HIDEMs and 3 WT adult skeletal muscle derived mesoangioblasts (controls).
2012-07-08 | E-GEOD-36098 | biostudies-arrayexpress
Project description:Alterations in RNA-splicing are a molecular hallmark of several neurological diseases, including muscular dystrophies where mutations in genes involved in RNA metabolism or characterised by alterations in RNA splicing have been described. Here, we present five patients from two unrelated families with a limb-girdle muscular dystrophy (LGMD) phenotype carrying a biallelic variant in SNUPN gene. Snurportin-1, the protein encoded by SNUPN, plays an important role in the nuclear transport of small nuclear ribonucleoproteins (snRNPs), essential components of the spliceosome. We combine deep phenotyping, including clinical features, histopathology and muscle magnetic resonance image (MRI), with functional studies in patient-derived cells and muscle biopsies to demonstrate that variants in SNUPN are the cause of a new type of LGMD according to current definition. Moreover, an in vivo model in Drosophila melanogaster further supports the relevance of Snurportin-1 in muscle. SNUPN patients show a similar phenotype characterised by proximal weakness starting in childhood, restrictive respiratory dysfunction and prominent contractures, although interindividual variability in terms of severity even in individuals from the same family was found. Muscle biopsy showed myofibrillar-like features consisting of myotilin deposits and Z-disc disorganisation. MRI showed predominant impairment of paravertebral, vasti, sartorius, gracilis, peroneal and medial gastrocnemius muscles. Conservation and structural analyses of Snurportin-1 p.Ile309Ser variant suggest an effect in nuclear-cytosol snRNP trafficking. In patient-derived fibroblasts and muscle, cytoplasmic accumulation of snRNP components is observed, while total expression of Snurportin-1 and snRNPs remains unchanged, which demonstrates a functional impact of SNUPN variant in snRNP metabolism. Furthermore, RNA-splicing analysis in patients’ muscle showed widespread splicing deregulation, in particular in genes relevant for muscle development and splicing factors that participate in the early steps of spliceosome assembly. In conclusion, we report that SNUPN variants are a new cause of limb girdle muscular dystrophy with specific clinical, histopathological and imaging features, supporting SNUPN as a new gene to be included in genetic testing of myopathies. These results further support the relevance of splicing-related proteins in muscle disorders.
2024-02-29 | GSE253519 | GEO
Project description:Even though genetic studies of individuals with neuromuscular diseases have uncovered the molecular background of many cardiac disorders such as cardiomyopathies and inherited arrhythmic syndromes, the genetic cause of a proportion of cardiomyopathies associated with neuromuscular phenotype still remains unknown. Here, we present a clinical case with a combination of cardiomyopathy and limb-girdle type muscular dystrophy where whole exome sequencing identified myoferlin (MYOF) - a member of the Ferlin protein family and close homolog of DYSF - as the most likely candidate gene. The disease-causative role of the identified variant c.[2576delG; 2575G>C], p.G859fs is supported by functional studies in vitro using primary patient's satellite cells, including both RNA sequencing and morphological studies, as well as recapitulating of muscle phenotype in vivo in zebrafish experiments. We provide the first evidence supporting a role of MYOF in human muscle disease.
2019-08-24 | GSE119027 | GEO
Project description:Human pelvic girdle, especially the ilium is considered an evolutionary novelty. To understand the genetic architecute behind the formation of this structure, we conducted single cell multiomics across developmental stages.
2025-07-04 | GSE281313 | GEO
Project description:Human pelvic girdle, especially the ilium is considered an evolutionary novelty. To understand the genetic architecute behind the formation of this structure, we conducted single cell multiomics across developmental stages.
2025-07-04 | GSE281317 | GEO
Project description:The sarcoglycan complex (SC) is part of a network that links the striated muscle cytoskeleton to the basal lamina across the sarcolemma. The SC coordinates changes in phosphorylation and Ca++-flux during mechanical deformation, and these processes are disrupted with loss-of-function mutations in gamma-sarcoglycan (Sgcg) that cause Limb Girdle Muscular Dystrophy 2C/R5. To gain insight into how the SC mediates mechano-signaling in muscle, we utilized LC-MS/MS proteomics to identify SC-associated proteins in immunoprecipitates from enriched sarcolemmal fractions. Criteria for inclusion were selective co-immunoprecipitation with anti-Sgcg from C57BL/6 control muscle, but under-representation in parallel experiments with Sgcg-null muscle or with non-specific IgG. Co-immunoprecipitation from archvillin-deleted muscle (Svil-null) was also evaluated.
2022-02-16 | PXD028584 | Pride
Project description:Mesoangioblasts are stem/progenitor cells derived from a subset of pericytes expressing alkaline phosphatase. They have been shown to ameliorate muscular dystrophies (currently incurable diseases) in different animal models and are now undergoing clinical experimentation for Duchenne muscular dystrophy. We show here that patients affected by limb-girdle muscular dystrophy 2D (LGMD2D, characterized by α-sarcoglycan deficit) have a reduction of this subset of pericytes and hence mesoangioblast could not be derived for cell therapy. Therefore, we reprogrammed LGMD2D fibroblasts and myoblasts to induced pluripotent stem cells (iPSCs) and developed a protocol for the derivation of mesoangioblast-like cells from them. These cells can be expanded and genetically corrected with a muscle-specific lentiviral vector expressing human α-sarcoglycan. Upon transplantation into ad hoc generated α-sarcoglycan-null immunodeficient mice, they generate myofibers expressing α-sarcoglycan. This approach may be useful for muscular dystrophies that show a reduction of resident progenitors and provides evidence of pre-clinical safety and efficacy of disease-specific iPSCs.
2012-07-09 | GSE36098 | GEO
Project description:Comparative analysis of gene expression levels from hindlimb muscle tissue from 8 week old mouse models for muscular dystrophy. We have used mouse models with dystrophin-, sarcoglycan-, sarcospan-, or dysferlin-deficiency. Keywords = muscular dystrophy Keywords: other
2005-11-24 | GSE2112 | GEO