{"gene":"SGCB","run_date":"2026-06-10T07:46:31","timeline":{"discoveries":[{"year":1998,"finding":"Loss of beta-sarcoglycan (SGCB) mutations (T151R, R91C) in LGMD2E patients results in loss of the entire sarcoglycan complex at the sarcolemma and also causes reduction of alpha-dystroglycan, indicating that the sarcoglycan complex stabilizes alpha-dystroglycan at the sarcolemma.","method":"Immunohistochemical and immunoblot analysis of patient muscle biopsies; genomic organization of SGCB determined by sequencing","journal":"Neuromuscular disorders : NMD","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical analysis of patient biopsies with multiple protein assays in single lab; functional inference from loss-of-function patient material","pmids":["9565988"],"is_preprint":false},{"year":1998,"finding":"SGCB is initially transcribed ubiquitously during human development and later becomes restricted to striated muscle, heart, and central nervous system; translation of sarcoglycans appears restricted to skeletal muscle despite broader transcription.","method":"In situ hybridization and immunodetection on human embryonic/fetal tissue sections at multiple developmental stages","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization experiment across developmental stages in human tissue, single lab with systematic spatial analysis","pmids":["9521867"],"is_preprint":false},{"year":2003,"finding":"Beta-sarcoglycanopathy (LGMD2E) patients with SGCB mutations show loss of all sarcoglycans on muscle biopsy and develop dilated cardiomyopathy, demonstrating that SGCB function is required in cardiac muscle as well as skeletal muscle.","method":"Immunohistochemistry and immunoblot on skeletal muscle biopsies; non-invasive cardiac examination (echocardiography) in six LGMD2E patients","journal":"Neuromuscular disorders : NMD","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct protein loss confirmed by immunoblot correlated with cardiac phenotype; single center, small cohort","pmids":["12868499"],"is_preprint":false},{"year":2015,"finding":"AAV-mediated delivery of a codon-optimized human SGCB transgene (scAAVrh74.tMCK.hSGCB) to LGMD2E (Sgcb-null) mouse limb muscles restored beta-sarcoglycan expression in 91.2% of fibers, re-assembled the sarcoglycan complex, protected the sarcolemma from Evans blue dye leakage, reduced fibrosis by ~42-43%, normalized fiber size, and improved tetanic force and resistance to eccentric contraction.","method":"Isolated limb delivery of AAV vector; immunofluorescence for sarcoglycan complex assembly; Evans blue dye permeability assay; histology (collagen staining, central nucleation); in situ muscle force measurement","journal":"Gene therapy","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal functional readouts (membrane integrity, complex assembly, force production, histopathology) in well-defined KO model with clear mechanistic link between SGCB restoration and phenotype rescue","pmids":["26214262"],"is_preprint":false},{"year":2017,"finding":"Systemic delivery of scAAV.MHCK7.hSGCB via tail vein in SGCB-knockout mice achieved 98.1% transgene expression across all muscles, restored sarcoglycan complex assembly, reduced serum creatine kinase by 85.5%, increased diaphragm force production by 94.4%, reduced kyphoscoliosis by 48.1%, and improved overall ambulation, without adverse effects in wild-type mice.","method":"Systemic AAV delivery; immunofluorescence for sarcoglycan complex; serum CK assay; diaphragm force measurement; open-field locomotor testing; spine X-ray; histopathology","journal":"Molecular therapy : the journal of the American Society of Gene Therapy","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal functional and histological readouts in SGCB KO model following systemic SGCB restoration; replicated mechanistic findings from prior isolated-limb study with systemic route","pmids":["28284983"],"is_preprint":false},{"year":2023,"finding":"Deep mutational scanning of all 6,340 possible amino acid changes in SGCB showed that variant functional scores (assessed by sarcoglycan complex cell surface localization) are bimodally distributed, perfectly predicted pathogenicity of known variants, and that amino acid positions intolerant to variation map to predicted inter-subunit SGC interaction interfaces, validating structural models of the four-protein transmembrane sarcoglycan complex.","method":"Deep mutational scanning; cell surface localization assay for the sarcoglycan complex (β-, α-, γ-, δ-sarcoglycan); in silico structural modeling validated by functional scores","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1 / Strong — comprehensive saturation mutagenesis with functional readout for all possible variants; structural predictions orthogonally validated; rigorous single study with thousands of variants tested","pmids":["37317968"],"is_preprint":false}],"current_model":"Beta-sarcoglycan (SGCB) is a transmembrane protein that assembles with α-, γ-, and δ-sarcoglycan into a four-protein sarcoglycan complex at the sarcolemma of skeletal and cardiac muscle; loss of SGCB disrupts the entire sarcoglycan complex and destabilizes alpha-dystroglycan at the membrane, causing progressive muscular dystrophy (LGMD2E) with cardiomyopathy, and deep mutational scanning has mapped the specific residues mediating inter-subunit interactions required for complex assembly and sarcolemmal localization."},"narrative":{"mechanistic_narrative":"Beta-sarcoglycan (SGCB) is a striated-muscle transmembrane protein that assembles with α-, γ-, and δ-sarcoglycan into a four-subunit sarcoglycan complex at the sarcolemma, and its loss destabilizes the entire complex and reduces alpha-dystroglycan at the membrane [PMID:9565988, PMID:37317968]. Although SGCB is transcribed broadly during early human development, expression becomes restricted to striated muscle, heart, and central nervous system, with sarcoglycan protein accumulation concentrated in muscle [PMID:9521867]. Pathogenic SGCB mutations eliminate all sarcoglycans from the sarcolemma and cause limb-girdle muscular dystrophy type 2E with dilated cardiomyopathy, establishing a requirement for SGCB in both skeletal and cardiac muscle [PMID:9565988, PMID:12868499]. AAV-mediated restoration of human SGCB in Sgcb-null mice re-assembles the sarcoglycan complex, protects the sarcolemma from membrane permeability, reduces fibrosis, and restores muscle force, directly linking SGCB to membrane integrity and contractile function [PMID:26214262, PMID:28284983]. Deep mutational scanning across all possible SGCB amino acid changes shows that variants intolerant to substitution cluster at predicted inter-subunit interaction interfaces, defining the residues that mediate complex assembly and cell-surface localization [PMID:37317968].","teleology":[{"year":1998,"claim":"Established that SGCB is not merely one of several sarcoglycans but is required for stability of the whole complex, and that the complex in turn anchors alpha-dystroglycan at the membrane.","evidence":"Immunohistochemistry and immunoblot of LGMD2E patient muscle biopsies carrying SGCB point mutations","pmids":["9565988"],"confidence":"Medium","gaps":["Loss-of-function inference from patient material does not resolve the order of complex assembly","Does not define which residues mediate inter-subunit contacts"]},{"year":1998,"claim":"Resolved the developmental and tissue expression pattern of SGCB, showing a shift from ubiquitous transcription to striated-muscle-restricted protein accumulation.","evidence":"In situ hybridization and immunodetection on staged human embryonic/fetal tissue sections","pmids":["9521867"],"confidence":"Medium","gaps":["Mechanism restricting protein accumulation to muscle despite broad transcription is unexplained","CNS functional role not addressed"]},{"year":2003,"claim":"Demonstrated that SGCB function extends beyond skeletal muscle, as loss causes dilated cardiomyopathy alongside sarcoglycan loss in muscle.","evidence":"Immunoblot/immunohistochemistry on biopsies plus echocardiography in six LGMD2E patients","pmids":["12868499"],"confidence":"Medium","gaps":["Small single-center cohort","Does not establish cardiac-autonomous mechanism distinct from skeletal disease"]},{"year":2015,"claim":"Provided causal evidence that restoring SGCB alone re-builds the complex and rescues membrane integrity and force, confirming SGCB as the limiting subunit in LGMD2E muscle.","evidence":"Isolated-limb AAV delivery of codon-optimized hSGCB in Sgcb-null mice with membrane permeability, force, and histology readouts","pmids":["26214262"],"confidence":"High","gaps":["Localized delivery does not address systemic or cardiac correction","Durability of rescue not defined"]},{"year":2017,"claim":"Extended SGCB restoration to a systemic, whole-body context, showing rescue of respiratory muscle function and ambulation, supporting therapeutic feasibility.","evidence":"Systemic tail-vein AAV delivery in SGCB-knockout mice with serum CK, diaphragm force, locomotion, and spine imaging","pmids":["28284983"],"confidence":"High","gaps":["Long-term immune and safety profile in disease-relevant species not addressed","Cardiac functional rescue not quantified"]},{"year":2023,"claim":"Mapped the functional sequence determinants of SGCB at single-residue resolution, defining the inter-subunit interfaces required for complex assembly and surface localization and enabling variant pathogenicity prediction.","evidence":"Deep mutational scanning of all 6,340 amino acid changes with sarcoglycan complex cell-surface localization readout and structural modeling","pmids":["37317968"],"confidence":"High","gaps":["Cell-surface assay may not capture all in vivo functions","Structural models validated functionally but not by experimental atomic structure"]},{"year":null,"claim":"The biochemical role of SGCB in the CNS and the mechanism coupling the sarcoglycan complex to downstream signaling or alpha-dystroglycan stabilization remain undefined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No direct enzymatic or signaling activity assigned to SGCB","CNS function not characterized in the available corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,3,5]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,3,5]}],"pathway":[{"term_id":"R-HSA-397014","term_label":"Muscle contraction","supporting_discovery_ids":[3,4]}],"complexes":["sarcoglycan complex"],"partners":["SGCA","SGCG","SGCD","DAG1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q16585","full_name":"Beta-sarcoglycan","aliases":["43 kDa dystrophin-associated glycoprotein","43DAG","A3b"],"length_aa":318,"mass_kda":34.8,"function":"Component of the sarcoglycan complex, a subcomplex of the dystrophin-glycoprotein complex which forms a link between the F-actin cytoskeleton and the extracellular matrix","subcellular_location":"Cell membrane, sarcolemma; Cytoplasm, cytoskeleton","url":"https://www.uniprot.org/uniprotkb/Q16585/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SGCB","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SGCB","total_profiled":1310},"omim":[{"mim_id":"608896","title":"SARCOGLYCAN, GAMMA; SGCG","url":"https://www.omim.org/entry/608896"},{"mim_id":"608099","title":"MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 3; LGMDR3","url":"https://www.omim.org/entry/608099"},{"mim_id":"607155","title":"MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (LIMB-GIRDLE), TYPE C, 5; MDDGC5","url":"https://www.omim.org/entry/607155"},{"mim_id":"604286","title":"MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 4; LGMDR4","url":"https://www.omim.org/entry/604286"},{"mim_id":"601411","title":"SARCOGLYCAN, DELTA; SGCD","url":"https://www.omim.org/entry/601411"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"skeletal muscle","ntpm":98.9}],"url":"https://www.proteinatlas.org/search/SGCB"},"hgnc":{"alias_symbol":["SGC","A3b"],"prev_symbol":["LGMD2E"]},"alphafold":{"accession":"Q16585","domains":[{"cath_id":"-","chopping":"59-112","consensus_level":"medium","plddt":86.8207,"start":59,"end":112}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q16585","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q16585-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q16585-F1-predicted_aligned_error_v6.png","plddt_mean":76.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SGCB","jax_strain_url":"https://www.jax.org/strain/search?query=SGCB"},"sequence":{"accession":"Q16585","fasta_url":"https://rest.uniprot.org/uniprotkb/Q16585.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q16585/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q16585"}},"corpus_meta":[{"pmid":"24567525","id":"PMC_24567525","title":"Stimulation of the soluble guanylate cyclase (sGC) inhibits fibrosis by blocking non-canonical TGFβ signalling.","date":"2014","source":"Annals of the rheumatic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/24567525","citation_count":108,"is_preprint":false},{"pmid":"31349651","id":"PMC_31349651","title":"Cannabidiol Induces Cell Cycle Arrest and Cell Apoptosis in Human Gastric Cancer SGC-7901 Cells.","date":"2019","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/31349651","citation_count":104,"is_preprint":false},{"pmid":"8632003","id":"PMC_8632003","title":"L-lactate dehydrogenase A4- and A3B isoforms are bona fide peroxisomal enzymes in rat liver. 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toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/31203647","citation_count":23,"is_preprint":false},{"pmid":"19370777","id":"PMC_19370777","title":"Inhibitory effect of acetylshikonin on human gastric carcinoma cell line SGC-7901 in vitro and in vivo.","date":"2009","source":"World journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/19370777","citation_count":23,"is_preprint":false},{"pmid":"29943819","id":"PMC_29943819","title":"P2Y12 shRNA treatment decreases SGC activation to relieve diabetic neuropathic pain in type 2 diabetes mellitus rats.","date":"2018","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/29943819","citation_count":23,"is_preprint":false},{"pmid":"28687063","id":"PMC_28687063","title":"LGMD2E is the most common type of sarcoglycanopathies in the Iranian population.","date":"2017","source":"Journal of neurogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/28687063","citation_count":22,"is_preprint":false},{"pmid":"37338574","id":"PMC_37338574","title":"Rosmarinic acid, the active component of Rubi Fructus, induces apoptosis of SGC-7901 and HepG2 cells through mitochondrial pathway and exerts anti-tumor effect.","date":"2023","source":"Naunyn-Schmiedeberg's archives of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/37338574","citation_count":22,"is_preprint":false},{"pmid":"28281969","id":"PMC_28281969","title":"CSTB Downregulation Promotes Cell Proliferation and Migration and Suppresses Apoptosis in Gastric Cancer SGC-7901 Cell Line.","date":"2016","source":"Oncology research","url":"https://pubmed.ncbi.nlm.nih.gov/28281969","citation_count":22,"is_preprint":false},{"pmid":"29535501","id":"PMC_29535501","title":"Integration of microRNA-mRNA profiles and pathway analysis of plant isoquinoline alkaloid berberine in SGC-7901 gastric cancers cells.","date":"2018","source":"Drug design, development and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/29535501","citation_count":22,"is_preprint":false},{"pmid":"29085478","id":"PMC_29085478","title":"Effect of FABP5 gene silencing on the proliferation, apoptosis and invasion of human gastric SGC-7901 cancer cells.","date":"2017","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/29085478","citation_count":22,"is_preprint":false},{"pmid":"36350314","id":"PMC_36350314","title":"Activating NO-sGC crosstalk in the mouse vascular niche promotes vascular integrity and mitigates acute lung injury.","date":"2022","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36350314","citation_count":21,"is_preprint":false},{"pmid":"31952789","id":"PMC_31952789","title":"A novel bispecific chimeric PD1-DAP10/NKG2D receptor augments NK92-cell therapy efficacy for human gastric cancer SGC-7901 cell.","date":"2020","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/31952789","citation_count":21,"is_preprint":false},{"pmid":"23794147","id":"PMC_23794147","title":"Targeted gene delivery with noncovalent electrostatic conjugates of sgc-8c aptamer and polyethylenimine.","date":"2013","source":"The journal of gene medicine","url":"https://pubmed.ncbi.nlm.nih.gov/23794147","citation_count":21,"is_preprint":false},{"pmid":"29845222","id":"PMC_29845222","title":"Paeonol induces the apoptosis of the SGC‑7901 gastric cancer cell line by downregulating ERBB2 and inhibiting the NF‑κB signaling pathway.","date":"2018","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29845222","citation_count":21,"is_preprint":false},{"pmid":"35524577","id":"PMC_35524577","title":"Solasonine induces apoptosis of the SGC-7901 human gastric cancer cell line in vitro via the mitochondria-mediated pathway.","date":"2022","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35524577","citation_count":20,"is_preprint":false},{"pmid":"36099983","id":"PMC_36099983","title":"Zhenwu decoction ameliorates cardiac hypertrophy through activating sGC (soluble guanylate cyclase) - cGMP (cyclic guanosine monophosphate) - PKG (protein kinase G) pathway.","date":"2022","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/36099983","citation_count":20,"is_preprint":false},{"pmid":"35845490","id":"PMC_35845490","title":"Soluble guanylate cyclase (sGC) stimulator vericiguat alleviates myocardial ischemia-reperfusion injury by improving microcirculation.","date":"2022","source":"Annals of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35845490","citation_count":20,"is_preprint":false},{"pmid":"30013646","id":"PMC_30013646","title":"Pachymic acid inhibits growth and induces cell cycle arrest and apoptosis in gastric cancer SGC-7901 cells.","date":"2018","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/30013646","citation_count":20,"is_preprint":false},{"pmid":"34487435","id":"PMC_34487435","title":"The Role of sGC Stimulators and Activators in Heart Failure With Reduced Ejection Fraction.","date":"2021","source":"Journal of cardiovascular pharmacology and therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/34487435","citation_count":19,"is_preprint":false},{"pmid":"31313530","id":"PMC_31313530","title":"Treatment of pediatric pulmonary arterial hypertension: A focus on the NO-sGC-cGMP pathway.","date":"2019","source":"Pediatric pulmonology","url":"https://pubmed.ncbi.nlm.nih.gov/31313530","citation_count":19,"is_preprint":false},{"pmid":"33215324","id":"PMC_33215324","title":"Arborinine, a potential LSD1 inhibitor, inhibits epithelial-mesenchymal transition of SGC-7901 cells and adriamycin-resistant gastric cancer SGC-7901/ADR cells.","date":"2020","source":"Investigational new drugs","url":"https://pubmed.ncbi.nlm.nih.gov/33215324","citation_count":19,"is_preprint":false},{"pmid":"26983679","id":"PMC_26983679","title":"Regulation of sGC via hsp90, Cellular Heme, sGC Agonists, and NO: New Pathways and Clinical Perspectives.","date":"2016","source":"Antioxidants & redox signaling","url":"https://pubmed.ncbi.nlm.nih.gov/26983679","citation_count":19,"is_preprint":false},{"pmid":"21354320","id":"PMC_21354320","title":"Activation of MEK1/ERK1/2/iNOS/sGC/PKG pathway associated with peroxynitrite formation contributes to hypotension and vascular hyporeactivity in endotoxemic rats.","date":"2011","source":"Nitric oxide : biology and chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21354320","citation_count":19,"is_preprint":false},{"pmid":"26677104","id":"PMC_26677104","title":"Chelidonine induces mitotic slippage and apoptotic-like death in SGC-7901 human gastric carcinoma cells.","date":"2015","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/26677104","citation_count":19,"is_preprint":false},{"pmid":"25015797","id":"PMC_25015797","title":"sGC-cGMP signaling: target for anticancer therapy.","date":"2014","source":"Advances in experimental medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/25015797","citation_count":18,"is_preprint":false},{"pmid":"23791669","id":"PMC_23791669","title":"Angiotensin AT2 receptor agonist stimulates high stretch induced- ANP secretion via PI3K/NO/sGC/PKG/pathway.","date":"2013","source":"Peptides","url":"https://pubmed.ncbi.nlm.nih.gov/23791669","citation_count":18,"is_preprint":false},{"pmid":"33681964","id":"PMC_33681964","title":"Peripheral arteriopathy caused by Notch3 gain-of-function mutation involves ER and oxidative stress and blunting of NO/sGC/cGMP pathway.","date":"2021","source":"Clinical science (London, England : 1979)","url":"https://pubmed.ncbi.nlm.nih.gov/33681964","citation_count":17,"is_preprint":false},{"pmid":"22024089","id":"PMC_22024089","title":"RNA interference mediated YAP gene silencing inhibits invasion and metastasis of human gastric cancer cell line SGC-7901.","date":"2011","source":"Hepato-gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/22024089","citation_count":17,"is_preprint":false},{"pmid":"32281434","id":"PMC_32281434","title":"Orbitides isolated from flaxseed induce apoptosis against SGC-7901 adenocarcinoma cells.","date":"2020","source":"International journal of food sciences and nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/32281434","citation_count":17,"is_preprint":false},{"pmid":"37317968","id":"PMC_37317968","title":"Comprehensive functional characterization of SGCB coding variants predicts pathogenicity in limb-girdle muscular dystrophy type R4/2E.","date":"2023","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/37317968","citation_count":16,"is_preprint":false},{"pmid":"28878687","id":"PMC_28878687","title":"NO-sGC Pathway Modulates Ca2+ Release and Muscle Contraction in Zebrafish Skeletal Muscle.","date":"2017","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/28878687","citation_count":16,"is_preprint":false},{"pmid":"30274346","id":"PMC_30274346","title":"LP1 from Lentinula edodes C91-3 Induces Autophagy, Apoptosis and Reduces Metastasis in Human Gastric Cancer Cell Line SGC-7901.","date":"2018","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30274346","citation_count":16,"is_preprint":false},{"pmid":"34151411","id":"PMC_34151411","title":"The sGC-cGMP Signaling Pathway as a Potential Therapeutic Target in Doxorubicin-Induced Heart Failure: A Narrative Review.","date":"2021","source":"American journal of cardiovascular drugs : drugs, devices, and other interventions","url":"https://pubmed.ncbi.nlm.nih.gov/34151411","citation_count":15,"is_preprint":false},{"pmid":"28222440","id":"PMC_28222440","title":"SUMO-1 Gene Silencing Inhibits Proliferation and Promotes Apoptosis of Human Gastric Cancer SGC-7901 Cells.","date":"2017","source":"Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/28222440","citation_count":15,"is_preprint":false},{"pmid":"38734687","id":"PMC_38734687","title":"Chronic circadian rhythm disorder induces heart failure with preserved ejection fraction-like phenotype through the Clock-sGC-cGMP-PKG1 signaling pathway.","date":"2024","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/38734687","citation_count":14,"is_preprint":false},{"pmid":"37686032","id":"PMC_37686032","title":"The sGC Activator Runcaciguat Has Kidney Protective Effects and Prevents a Decline of Kidney Function in ZSF1 Rats.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37686032","citation_count":14,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":56049,"output_tokens":2161,"usd":0.100281,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8534,"output_tokens":2168,"usd":0.048435,"stage2_stop_reason":"end_turn"},"total_usd":0.148716,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to identify papers about SGCB (beta-sarcoglycan, the gene causing LGMD2E) versus the many papers about sGC (soluble guanylate cyclase) and SGC-7901 (a gastric cancer cell line). These are completely different entities.\n\nSGCB = beta-sarcoglycan, a muscle membrane protein component of the dystrophin-glycoprotein complex.\nsGC = soluble guanylate cyclase (GUCY1A1/GUCY1B1 genes) — different gene entirely.\nSGC-7901 = a gastric cancer cell line — not a gene at all.\n\nPapers relevant to SGCB (beta-sarcoglycan): [9], [15], [17], [25], [50], [52] (mentions SGCB in a lncRNA context - non-protein product study), [70], [94], [95] (zebrafish NO-sGC pathway in skeletal muscle - about soluble guanylate cyclase, not sarcoglycan).\n\nPaper [52] mentions SGCB as a pathway component in trophoblast apoptosis - but this appears to be about soluble guanylate cyclase beta subunit, not beta-sarcoglycan. The \"IP3R1/CaMKII/SGCB pathway\" context suggests this is NOT beta-sarcoglycan but rather the sGC beta subunit — this is a different protein.\n\nLet me focus on papers clearly about beta-sarcoglycan (SGCB/LGMD2E):\n- [9]: AAV gene therapy in SGCB knockout mice\n- [15]: Developmental expression of SGCB\n- [17]: Cardiac involvement in LGMD2E patients\n- [25]: Genomic organization, missense mutations, sarcoglycan complex analysis\n- [50]: AAV gene therapy in LGMD2E mice\n- [70]: Mutation spectrum in Iranian LGMD2E patients\n- [94]: Deep mutational scanning of SGCB, SGC complex localization\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"Loss of beta-sarcoglycan (SGCB) mutations (T151R, R91C) in LGMD2E patients results in loss of the entire sarcoglycan complex at the sarcolemma and also causes reduction of alpha-dystroglycan, indicating that the sarcoglycan complex stabilizes alpha-dystroglycan at the sarcolemma.\",\n      \"method\": \"Immunohistochemical and immunoblot analysis of patient muscle biopsies; genomic organization of SGCB determined by sequencing\",\n      \"journal\": \"Neuromuscular disorders : NMD\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical analysis of patient biopsies with multiple protein assays in single lab; functional inference from loss-of-function patient material\",\n      \"pmids\": [\"9565988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"SGCB is initially transcribed ubiquitously during human development and later becomes restricted to striated muscle, heart, and central nervous system; translation of sarcoglycans appears restricted to skeletal muscle despite broader transcription.\",\n      \"method\": \"In situ hybridization and immunodetection on human embryonic/fetal tissue sections at multiple developmental stages\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization experiment across developmental stages in human tissue, single lab with systematic spatial analysis\",\n      \"pmids\": [\"9521867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Beta-sarcoglycanopathy (LGMD2E) patients with SGCB mutations show loss of all sarcoglycans on muscle biopsy and develop dilated cardiomyopathy, demonstrating that SGCB function is required in cardiac muscle as well as skeletal muscle.\",\n      \"method\": \"Immunohistochemistry and immunoblot on skeletal muscle biopsies; non-invasive cardiac examination (echocardiography) in six LGMD2E patients\",\n      \"journal\": \"Neuromuscular disorders : NMD\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protein loss confirmed by immunoblot correlated with cardiac phenotype; single center, small cohort\",\n      \"pmids\": [\"12868499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"AAV-mediated delivery of a codon-optimized human SGCB transgene (scAAVrh74.tMCK.hSGCB) to LGMD2E (Sgcb-null) mouse limb muscles restored beta-sarcoglycan expression in 91.2% of fibers, re-assembled the sarcoglycan complex, protected the sarcolemma from Evans blue dye leakage, reduced fibrosis by ~42-43%, normalized fiber size, and improved tetanic force and resistance to eccentric contraction.\",\n      \"method\": \"Isolated limb delivery of AAV vector; immunofluorescence for sarcoglycan complex assembly; Evans blue dye permeability assay; histology (collagen staining, central nucleation); in situ muscle force measurement\",\n      \"journal\": \"Gene therapy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal functional readouts (membrane integrity, complex assembly, force production, histopathology) in well-defined KO model with clear mechanistic link between SGCB restoration and phenotype rescue\",\n      \"pmids\": [\"26214262\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Systemic delivery of scAAV.MHCK7.hSGCB via tail vein in SGCB-knockout mice achieved 98.1% transgene expression across all muscles, restored sarcoglycan complex assembly, reduced serum creatine kinase by 85.5%, increased diaphragm force production by 94.4%, reduced kyphoscoliosis by 48.1%, and improved overall ambulation, without adverse effects in wild-type mice.\",\n      \"method\": \"Systemic AAV delivery; immunofluorescence for sarcoglycan complex; serum CK assay; diaphragm force measurement; open-field locomotor testing; spine X-ray; histopathology\",\n      \"journal\": \"Molecular therapy : the journal of the American Society of Gene Therapy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal functional and histological readouts in SGCB KO model following systemic SGCB restoration; replicated mechanistic findings from prior isolated-limb study with systemic route\",\n      \"pmids\": [\"28284983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Deep mutational scanning of all 6,340 possible amino acid changes in SGCB showed that variant functional scores (assessed by sarcoglycan complex cell surface localization) are bimodally distributed, perfectly predicted pathogenicity of known variants, and that amino acid positions intolerant to variation map to predicted inter-subunit SGC interaction interfaces, validating structural models of the four-protein transmembrane sarcoglycan complex.\",\n      \"method\": \"Deep mutational scanning; cell surface localization assay for the sarcoglycan complex (β-, α-, γ-, δ-sarcoglycan); in silico structural modeling validated by functional scores\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — comprehensive saturation mutagenesis with functional readout for all possible variants; structural predictions orthogonally validated; rigorous single study with thousands of variants tested\",\n      \"pmids\": [\"37317968\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Beta-sarcoglycan (SGCB) is a transmembrane protein that assembles with α-, γ-, and δ-sarcoglycan into a four-protein sarcoglycan complex at the sarcolemma of skeletal and cardiac muscle; loss of SGCB disrupts the entire sarcoglycan complex and destabilizes alpha-dystroglycan at the membrane, causing progressive muscular dystrophy (LGMD2E) with cardiomyopathy, and deep mutational scanning has mapped the specific residues mediating inter-subunit interactions required for complex assembly and sarcolemmal localization.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"Beta-sarcoglycan (SGCB) is a striated-muscle transmembrane protein that assembles with α-, γ-, and δ-sarcoglycan into a four-subunit sarcoglycan complex at the sarcolemma, and its loss destabilizes the entire complex and reduces alpha-dystroglycan at the membrane [#0, #5]. Although SGCB is transcribed broadly during early human development, expression becomes restricted to striated muscle, heart, and central nervous system, with sarcoglycan protein accumulation concentrated in muscle [#1]. Pathogenic SGCB mutations eliminate all sarcoglycans from the sarcolemma and cause limb-girdle muscular dystrophy type 2E with dilated cardiomyopathy, establishing a requirement for SGCB in both skeletal and cardiac muscle [#0, #2]. AAV-mediated restoration of human SGCB in Sgcb-null mice re-assembles the sarcoglycan complex, protects the sarcolemma from membrane permeability, reduces fibrosis, and restores muscle force, directly linking SGCB to membrane integrity and contractile function [#3, #4]. Deep mutational scanning across all possible SGCB amino acid changes shows that variants intolerant to substitution cluster at predicted inter-subunit interaction interfaces, defining the residues that mediate complex assembly and cell-surface localization [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established that SGCB is not merely one of several sarcoglycans but is required for stability of the whole complex, and that the complex in turn anchors alpha-dystroglycan at the membrane.\",\n      \"evidence\": \"Immunohistochemistry and immunoblot of LGMD2E patient muscle biopsies carrying SGCB point mutations\",\n      \"pmids\": [\"9565988\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Loss-of-function inference from patient material does not resolve the order of complex assembly\", \"Does not define which residues mediate inter-subunit contacts\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Resolved the developmental and tissue expression pattern of SGCB, showing a shift from ubiquitous transcription to striated-muscle-restricted protein accumulation.\",\n      \"evidence\": \"In situ hybridization and immunodetection on staged human embryonic/fetal tissue sections\",\n      \"pmids\": [\"9521867\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism restricting protein accumulation to muscle despite broad transcription is unexplained\", \"CNS functional role not addressed\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstrated that SGCB function extends beyond skeletal muscle, as loss causes dilated cardiomyopathy alongside sarcoglycan loss in muscle.\",\n      \"evidence\": \"Immunoblot/immunohistochemistry on biopsies plus echocardiography in six LGMD2E patients\",\n      \"pmids\": [\"12868499\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Small single-center cohort\", \"Does not establish cardiac-autonomous mechanism distinct from skeletal disease\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Provided causal evidence that restoring SGCB alone re-builds the complex and rescues membrane integrity and force, confirming SGCB as the limiting subunit in LGMD2E muscle.\",\n      \"evidence\": \"Isolated-limb AAV delivery of codon-optimized hSGCB in Sgcb-null mice with membrane permeability, force, and histology readouts\",\n      \"pmids\": [\"26214262\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Localized delivery does not address systemic or cardiac correction\", \"Durability of rescue not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended SGCB restoration to a systemic, whole-body context, showing rescue of respiratory muscle function and ambulation, supporting therapeutic feasibility.\",\n      \"evidence\": \"Systemic tail-vein AAV delivery in SGCB-knockout mice with serum CK, diaphragm force, locomotion, and spine imaging\",\n      \"pmids\": [\"28284983\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Long-term immune and safety profile in disease-relevant species not addressed\", \"Cardiac functional rescue not quantified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Mapped the functional sequence determinants of SGCB at single-residue resolution, defining the inter-subunit interfaces required for complex assembly and surface localization and enabling variant pathogenicity prediction.\",\n      \"evidence\": \"Deep mutational scanning of all 6,340 amino acid changes with sarcoglycan complex cell-surface localization readout and structural modeling\",\n      \"pmids\": [\"37317968\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-surface assay may not capture all in vivo functions\", \"Structural models validated functionally but not by experimental atomic structure\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The biochemical role of SGCB in the CNS and the mechanism coupling the sarcoglycan complex to downstream signaling or alpha-dystroglycan stabilization remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct enzymatic or signaling activity assigned to SGCB\", \"CNS function not characterized in the available corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 3, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-397014\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"complexes\": [\"sarcoglycan complex\"],\n    \"partners\": [\"SGCA\", \"SGCG\", \"SGCD\", \"DAG1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}