{"gene":"JPH1","run_date":"2026-04-28T18:06:54","timeline":{"discoveries":[{"year":2000,"finding":"JPH1 (JP-1) was identified as a founding member of the junctophilin family of junctional membrane complex proteins. JPH1 is composed of a C-terminal hydrophobic segment that spans the sarcoplasmic reticulum (SR) membrane and a cytoplasmic domain with specific affinity for the plasma membrane (T-tubule), thereby physically bridging T-tubules and SR to form junctional membrane complexes essential for excitation-contraction coupling.","method":"Molecular cloning, expression analysis, subcellular fractionation, and characterization of mutant mice lacking JP-2 (which demonstrated deficiency of junctional membrane complexes and abnormal Ca2+ transients, validating the family's role)","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 — founding study with molecular cloning, localization, and in vivo genetic validation; replicated in subsequent work","pmids":["10949023"],"is_preprint":false},{"year":2007,"finding":"JPH1 physically interacts with the RyR1 channel complex in a conformationally sensitive manner. Co-immunoprecipitation demonstrated a direct JP1–RyR1 interaction that depends on the conformational/gating state of RyR1. Three hyper-reactive cysteine residues of JPH1 (Cys101, Cys402, Cys627) were identified as redox-sensitive thiols whose chemical status modulates this interaction, suggesting JPH1 contributes integral redox-sensing properties to the RyR1 complex.","method":"Co-immunoprecipitation, fluorescent thiol-reactive probe labeling (DAMP), preparative SDS-PAGE, in-gel tryptic digestion, HPLC, and mass spectrometry-based peptide sequencing","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — reciprocal Co-IP combined with MS-based cysteine mapping and functional redox modulation experiments in a single study with multiple orthogonal methods","pmids":["17237236"],"is_preprint":false},{"year":2012,"finding":"JPH1 undergoes Ca2+-dependent proteolysis mediated by endogenous μ-calpain over the physiological Ca2+ concentration range in skeletal muscle. Cleavage occurs near the C-terminus, yielding a ~75 kDa diffusible fragment and a fixed ~15 kDa SR-embedded fragment. This proteolysis is associated with failure of excitation-contraction coupling: depolarization-induced force responses in skinned rat fibres were abolished following high-Ca2+ exposure coincident with loss of full-length JPH1. Supraphysiological stimulation (repeated tetanic stimulation + caffeine) also produced marked JP1 proteolysis in vitro, and JP1 proteolysis was observed in dystrophic mdx limb muscles at 4 weeks of age.","method":"Biochemical fractionation of skeletal muscle homogenates at precisely set [Ca2+], immunoblotting, skinned fibre force measurements, in vitro muscle stimulation, and mdx mouse model analysis","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (biochemical cleavage assays, functional force measurements, disease model) in a single rigorous study","pmids":["23148318"],"is_preprint":false},{"year":2024,"finding":"Homozygous loss-of-function variants in JPH1 (stop-gain and frameshift mutations) cause congenital myopathy with prominent facial, ocular, and bulbar involvement in humans. Ultrastructural analysis of patient muscle biopsies revealed slightly reduced triads and structurally abnormal sarcoplasmic reticulum, directly linking JPH1 loss to defective triad junction formation and establishing JPH1 as essential for connecting the SR and T-tubules in skeletal muscle.","method":"Exome/genome sequencing, RNA-seq with gene expression outlier analysis, muscle biopsy ultrastructural analysis (electron microscopy)","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 — human genetics with ultrastructural validation; four unrelated families; single study","pmids":["39209426"],"is_preprint":false},{"year":2024,"finding":"RNAi-mediated knockdown of the C. elegans JPH1 ortholog jph-1 via bacterial feeding altered nervous system physical morphology and impaired thrashing locomotion (muscle endurance), demonstrating a conserved role for junctophilin-1 in muscle physiology and neuronal structure in vivo.","method":"RNAi knockdown by bacterial feeding, phenotypic analysis of nervous system morphology and thrashing locomotion assay in C. elegans","journal":"microPublication biology","confidence":"Low","confidence_rationale":"Tier 3 — single method (RNAi) with phenotypic readout, no molecular pathway placement","pmids":["39381635"],"is_preprint":false}],"current_model":"JPH1 (junctophilin-1) is a structural protein anchored in the sarcoplasmic reticulum membrane via its C-terminal hydrophobic segment whose cytoplasmic domain bridges T-tubules and SR to form junctional membrane complexes essential for excitation-contraction coupling in skeletal muscle; it physically interacts with the RyR1 Ca2+-release channel in a conformationally and redox-sensitive manner through hyper-reactive cysteine residues (Cys101, Cys402, Cys627), and is subject to Ca2+-dependent proteolysis by μ-calpain near its C-terminus, a mechanism that disrupts EC coupling under conditions of Ca2+ overload or dystrophic disease."},"narrative":{"teleology":[{"year":2000,"claim":"The identification of junctophilins as a protein family established that a dedicated structural molecule tethers the SR to T-tubules, answering how junctional membrane complexes critical for EC coupling are physically maintained.","evidence":"Molecular cloning, subcellular fractionation, and JP-2-null mouse analysis demonstrating loss of junctional membrane complexes","pmids":["10949023"],"confidence":"High","gaps":["No direct JPH1 knockout phenotype characterized at this stage","Identity of JPH1's channel interaction partners unknown","Mechanism of plasma membrane binding by the cytoplasmic domain unresolved"]},{"year":2007,"claim":"Demonstrating a direct, conformation-sensitive JPH1–RyR1 interaction with redox-sensitive cysteines revealed that JPH1 is not merely a passive tether but an integral component of the Ca²⁺-release channel complex capable of sensing oxidative stress.","evidence":"Co-immunoprecipitation and mass spectrometry–based cysteine mapping with thiol-reactive probes in skeletal muscle preparations","pmids":["17237236"],"confidence":"High","gaps":["Functional consequences of cysteine oxidation on EC coupling not directly measured","No structural model of the JPH1–RyR1 interface","Whether redox modification of JPH1 occurs in vivo under physiological or pathological conditions was not tested"]},{"year":2012,"claim":"Identification of µ-calpain–mediated proteolysis of JPH1 at pathological Ca²⁺ levels, coincident with loss of depolarization-induced force, established a molecular mechanism by which Ca²⁺ overload dismantles the triad junction and disables EC coupling.","evidence":"Biochemical fractionation at defined [Ca²⁺], skinned fibre force measurements, in vitro stimulation, and immunoblotting in wild-type and mdx mouse muscle","pmids":["23148318"],"confidence":"High","gaps":["Exact calpain cleavage site(s) in JPH1 not mapped at residue resolution","Whether the released ~75 kDa fragment has any signaling role (as reported for JPH2 N-terminal fragments) is unknown","Contribution of JPH1 proteolysis versus other calpain substrates to EC coupling failure not dissected"]},{"year":2024,"claim":"Discovery of biallelic JPH1 loss-of-function variants causing human congenital myopathy with triad abnormalities demonstrated that JPH1 is non-redundant with JPH2 in skeletal muscle and is required for normal triad formation in humans.","evidence":"Exome/genome sequencing in four unrelated families, RNA-seq expression outlier analysis, and electron microscopy of patient muscle biopsies","pmids":["39209426"],"confidence":"Medium","gaps":["Single study; independent replication in additional cohorts not yet available","Genotype–phenotype correlations across different JPH1 variant types not established","Whether residual JPH2 partially compensates in affected patients is uncharacterized"]},{"year":null,"claim":"Key unresolved questions include the atomic-resolution structure of JPH1 (alone and in complex with RyR1), the precise calpain cleavage site(s), the in vivo functional consequences of JPH1 cysteine oxidation, and whether the proteolytic N-terminal fragment has nuclear or signaling roles analogous to those described for JPH2.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of any junctophilin-1 domain or complex","Potential nuclear translocation of cleavage fragments untested for JPH1","Therapeutic strategies to prevent JPH1 proteolysis in dystrophic or overloaded muscle not explored"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,3]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,2,3]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-397014","term_label":"Muscle contraction","supporting_discovery_ids":[0,1,2,3]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3]}],"complexes":[],"partners":["RYR1"],"other_free_text":[]},"mechanistic_narrative":"JPH1 (junctophilin-1) is a structural membrane-tethering protein that physically bridges the sarcoplasmic reticulum (SR) and T-tubule plasma membrane to form junctional membrane complexes essential for excitation–contraction (EC) coupling in skeletal muscle [PMID:10949023]. Its C-terminal hydrophobic segment anchors in the SR membrane while its cytoplasmic domain binds the T-tubule; this domain also directly interacts with the RyR1 Ca²⁺-release channel in a conformation- and redox-sensitive manner through hyper-reactive cysteine residues (Cys101, Cys402, Cys627) [PMID:17237236]. JPH1 is subject to Ca²⁺-dependent proteolysis by µ-calpain near its C-terminus, which disrupts EC coupling and is observed in dystrophic muscle [PMID:23148318]. Homozygous loss-of-function variants in JPH1 cause congenital myopathy with defective triad junction formation in humans [PMID:39209426]."},"prefetch_data":{"uniprot":{"accession":"Q9HDC5","full_name":"Junctophilin-1","aliases":["Junctophilin type 1"],"length_aa":661,"mass_kda":71.7,"function":"Junctophilins contribute to the formation of junctional membrane complexes (JMCs) which link the plasma membrane with the endoplasmic or sarcoplasmic reticulum in excitable cells. Provides a structural foundation for functional cross-talk between the cell surface and intracellular calcium release channels. JPH1 contributes to the construction of the skeletal muscle triad by linking the t-tubule (transverse-tubule) and SR (sarcoplasmic reticulum) membranes","subcellular_location":"Cell membrane; Endoplasmic reticulum membrane; Sarcoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q9HDC5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/JPH1","classification":"Not Classified","n_dependent_lines":11,"n_total_lines":1208,"dependency_fraction":0.009105960264900662},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"TMED10","stoichiometry":0.2},{"gene":"CCDC47","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/JPH1","total_profiled":1310},"omim":[{"mim_id":"620964","title":"CONGENITAL MYOPATHY 25; CMYO25","url":"https://www.omim.org/entry/620964"},{"mim_id":"615093","title":"LYMPHOCYTE ANTIGEN 6 COMPLEX, LOCUS K; LY6K","url":"https://www.omim.org/entry/615093"},{"mim_id":"607831","title":"CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2K; CMT2K","url":"https://www.omim.org/entry/607831"},{"mim_id":"606598","title":"GANGLIOSIDE-INDUCED DIFFERENTIATION-ASSOCIATED PROTEIN 1; GDAP1","url":"https://www.omim.org/entry/606598"},{"mim_id":"605267","title":"JUNCTOPHILIN 2; JPH2","url":"https://www.omim.org/entry/605267"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"skeletal muscle","ntpm":222.3},{"tissue":"tongue","ntpm":99.1}],"url":"https://www.proteinatlas.org/search/JPH1"},"hgnc":{"alias_symbol":["JP-1","JP1"],"prev_symbol":[]},"alphafold":{"accession":"Q9HDC5","domains":[{"cath_id":"3.90.930","chopping":"1-154_275-426","consensus_level":"medium","plddt":92.3511,"start":1,"end":426}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HDC5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HDC5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HDC5-F1-predicted_aligned_error_v6.png","plddt_mean":65.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=JPH1","jax_strain_url":"https://www.jax.org/strain/search?query=JPH1"},"sequence":{"accession":"Q9HDC5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9HDC5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9HDC5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HDC5"}},"corpus_meta":[{"pmid":"2961609","id":"PMC_2961609","title":"Rearrangements to the JP1, JP and JP2 segments in the human T-cell rearranging gamma gene (TRG gamma) locus.","date":"1987","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/2961609","citation_count":134,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25091324","id":"PMC_25091324","title":"Anaerobic biodegradation of high-molecular-weight polycyclic aromatic hydrocarbons by a facultative anaerobe Pseudomonas sp. 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Cys627). The JP1–RyR1 complex stability is sensitive to RyR1 gating state and redox status of these cysteines, suggesting JP1 contributes redox-sensing properties to the RyR1 channel complex.\",\n      \"method\": \"Co-immunoprecipitation, fluorescent thiol-reactive probe labeling, preparative SDS-PAGE, in-gel tryptic digestion, HPLC, and mass spectrometry-based peptide sequencing\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (Co-IP, MS-based site identification, thiol chemistry) in a single rigorous study identifying specific cysteine residues\",\n      \"pmids\": [\"17237236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Loss-of-function variants in JPH1 (homozygous stop-gain and frameshift mutations) cause congenital myopathy with prominent facial, ocular, and bulbar involvement, associated with reduced triads and structurally abnormal sarcoplasmic reticulum on electron microscopy, establishing JPH1 as essential for skeletal muscle triad junction formation by connecting the sarcoplasmic reticulum and T-tubules.\",\n      \"method\": \"Exome/genome sequencing, muscle biopsy ultrastructural analysis, RNA-seq with gene expression outlier analysis\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — four independent loss-of-function families with consistent ultrastructural phenotype (reduced/abnormal triads) and RNA-seq confirmation; replicated across unrelated probands\",\n      \"pmids\": [\"39209426\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RNAi-mediated knockdown of jph-1 (C. elegans JPH1 ortholog) alters nervous system morphology and impairs muscle endurance (thrashing locomotion), supporting a conserved role for junctophilin-1 in muscle physiology and calcium signaling.\",\n      \"method\": \"RNAi by bacterial feeding, locomotion assay, morphological analysis\",\n      \"journal\": \"microPublication biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean knockdown with defined cellular/behavioral phenotype in a model organism ortholog, but single lab, single organism\",\n      \"pmids\": [\"39381635\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"JPH1 (junctophilin-1) is a skeletal muscle triad protein that physically bridges the sarcoplasmic reticulum and T-tubule membranes, interacting with RyR1 through conformation-sensitive hyper-reactive cysteine thiols to regulate excitation-contraction coupling; loss of JPH1 disrupts triad structure and calcium homeostasis, causing congenital myopathy.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper first, then extract discoveries only from KEEP papers.\n\n**Classification:**\n\nRetrieved papers:\n1. PMID:2961609 — TCR gamma gene JP1 segment (T-cell receptor gene segment, not JPH1 protein) → EXCLUDE (alias collision)\n2. PMID:25091324 — Pseudomonas sp. JP1 (bacteria) → EXCLUDE (symbol collision)\n3. PMID:17237236 — Junctophilin 1 (JP1) and RyR1 → KEEP (canonical JPH1)\n4. PMID:15466523 — Pseudomonas aeruginosa JP1 mutant (bacteria) → EXCLUDE (symbol collision)\n5. PMID:32724456 — JP1 peptide from JWA protein → EXCLUDE (alias collision; JP1 here is a JWA-derived peptide, not junctophilin-1)\n6. PMID:22892884 — Saccharomyces cerevisiae JP1 strain → EXCLUDE (symbol collision)\n7. PMID:28074102 — Chinese herbal formula JP-1 → EXCLUDE (alias collision)\n8. PMID:30804591 — JPH1 SNP and CMT2K → KEEP (canonical JPH1, genetic modifier study)\n9. PMID:36280689 — JP1 peptide targeting integrin αVβ3 → EXCLUDE (alias collision; JP1 is JWA-derived peptide)\n10. PMID:2470614 — TCR gamma JP1 rearrangement → EXCLUDE (alias collision)\n11. PMID:39209426 — Loss-of-function variants in JPH1 → KEEP (canonical JPH1)\n12. PMID:38370827 — Loss-of-function variants in JPH1 (preprint) → KEEP (canonical JPH1)\n13. PMID:39381635 — C. elegans jph-1 knockdown → KEEP (ortholog, consistent function)\n14. PMID:31776220 — Mycobacterium JP-H-1 genome → EXCLUDE (symbol collision)\n\nGene2pubmed curated papers:\n- PMID:10949023 — Junctophilins novel family → KEEP (canonical JPH1 founding paper)\n- PMID:23148318 — Ca2+-dependent proteolysis of junctophilin-1 → KEEP (canonical JPH1)\n- All others (phosphoproteomics, interactome maps, cDNA libraries, etc.) → EXCLUDE (large-scale screens; JPH1 detected incidentally, no mechanistic findings specific to JPH1)\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"JPH1 (JP-1) was identified as a founding member of the junctophilin family of junctional membrane complex proteins. JPH1 is composed of a C-terminal hydrophobic segment that spans the sarcoplasmic reticulum (SR) membrane and a cytoplasmic domain with specific affinity for the plasma membrane (T-tubule), thereby physically bridging T-tubules and SR to form junctional membrane complexes essential for excitation-contraction coupling.\",\n      \"method\": \"Molecular cloning, expression analysis, subcellular fractionation, and characterization of mutant mice lacking JP-2 (which demonstrated deficiency of junctional membrane complexes and abnormal Ca2+ transients, validating the family's role)\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — founding study with molecular cloning, localization, and in vivo genetic validation; replicated in subsequent work\",\n      \"pmids\": [\"10949023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"JPH1 physically interacts with the RyR1 channel complex in a conformationally sensitive manner. Co-immunoprecipitation demonstrated a direct JP1–RyR1 interaction that depends on the conformational/gating state of RyR1. Three hyper-reactive cysteine residues of JPH1 (Cys101, Cys402, Cys627) were identified as redox-sensitive thiols whose chemical status modulates this interaction, suggesting JPH1 contributes integral redox-sensing properties to the RyR1 complex.\",\n      \"method\": \"Co-immunoprecipitation, fluorescent thiol-reactive probe labeling (DAMP), preparative SDS-PAGE, in-gel tryptic digestion, HPLC, and mass spectrometry-based peptide sequencing\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — reciprocal Co-IP combined with MS-based cysteine mapping and functional redox modulation experiments in a single study with multiple orthogonal methods\",\n      \"pmids\": [\"17237236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"JPH1 undergoes Ca2+-dependent proteolysis mediated by endogenous μ-calpain over the physiological Ca2+ concentration range in skeletal muscle. Cleavage occurs near the C-terminus, yielding a ~75 kDa diffusible fragment and a fixed ~15 kDa SR-embedded fragment. This proteolysis is associated with failure of excitation-contraction coupling: depolarization-induced force responses in skinned rat fibres were abolished following high-Ca2+ exposure coincident with loss of full-length JPH1. Supraphysiological stimulation (repeated tetanic stimulation + caffeine) also produced marked JP1 proteolysis in vitro, and JP1 proteolysis was observed in dystrophic mdx limb muscles at 4 weeks of age.\",\n      \"method\": \"Biochemical fractionation of skeletal muscle homogenates at precisely set [Ca2+], immunoblotting, skinned fibre force measurements, in vitro muscle stimulation, and mdx mouse model analysis\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (biochemical cleavage assays, functional force measurements, disease model) in a single rigorous study\",\n      \"pmids\": [\"23148318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Homozygous loss-of-function variants in JPH1 (stop-gain and frameshift mutations) cause congenital myopathy with prominent facial, ocular, and bulbar involvement in humans. Ultrastructural analysis of patient muscle biopsies revealed slightly reduced triads and structurally abnormal sarcoplasmic reticulum, directly linking JPH1 loss to defective triad junction formation and establishing JPH1 as essential for connecting the SR and T-tubules in skeletal muscle.\",\n      \"method\": \"Exome/genome sequencing, RNA-seq with gene expression outlier analysis, muscle biopsy ultrastructural analysis (electron microscopy)\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — human genetics with ultrastructural validation; four unrelated families; single study\",\n      \"pmids\": [\"39209426\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RNAi-mediated knockdown of the C. elegans JPH1 ortholog jph-1 via bacterial feeding altered nervous system physical morphology and impaired thrashing locomotion (muscle endurance), demonstrating a conserved role for junctophilin-1 in muscle physiology and neuronal structure in vivo.\",\n      \"method\": \"RNAi knockdown by bacterial feeding, phenotypic analysis of nervous system morphology and thrashing locomotion assay in C. elegans\",\n      \"journal\": \"microPublication biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single method (RNAi) with phenotypic readout, no molecular pathway placement\",\n      \"pmids\": [\"39381635\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"JPH1 (junctophilin-1) is a structural protein anchored in the sarcoplasmic reticulum membrane via its C-terminal hydrophobic segment whose cytoplasmic domain bridges T-tubules and SR to form junctional membrane complexes essential for excitation-contraction coupling in skeletal muscle; it physically interacts with the RyR1 Ca2+-release channel in a conformationally and redox-sensitive manner through hyper-reactive cysteine residues (Cys101, Cys402, Cys627), and is subject to Ca2+-dependent proteolysis by μ-calpain near its C-terminus, a mechanism that disrupts EC coupling under conditions of Ca2+ overload or dystrophic disease.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"JPH1 (junctophilin-1) is a structural tethering protein that physically bridges the sarcoplasmic reticulum and T-tubule membranes to form triad junctions essential for skeletal muscle excitation-contraction coupling [PMID:39209426]. JPH1 interacts with the ryanodine receptor RyR1 in a conformation- and redox-dependent manner, mediated by hyper-reactive cysteine residues (Cys101, Cys402, Cys627), linking the RyR1 gating state to redox sensing at the triad [PMID:17237236]. Loss-of-function mutations in JPH1 cause congenital myopathy with facial, ocular, and bulbar involvement, characterized by reduced triads and structurally abnormal sarcoplasmic reticulum [PMID:39209426].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Establishing how JPH1 physically couples to the calcium release channel: the discovery that JPH1 binds RyR1 through specific hyper-reactive cysteines in a conformation- and redox-sensitive manner revealed that JPH1 is not merely a passive membrane tether but an active sensor within the RyR1 complex.\",\n      \"evidence\": \"Co-immunoprecipitation, fluorescent thiol-reactive probe labeling, and mass spectrometry-based cysteine identification in skeletal muscle preparations\",\n      \"pmids\": [\"17237236\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of the JPH1–RyR1 interface beyond identified cysteines is unresolved\",\n        \"Functional consequence of cysteine oxidation on excitation-contraction coupling was not directly measured\",\n        \"Whether other junctophilin family members share the same redox-sensitive interaction mode is unknown\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrating that JPH1 is essential for triad junction integrity in human skeletal muscle and that its loss causes disease: identification of homozygous loss-of-function variants across four independent families linked JPH1 deficiency to congenital myopathy with reduced/abnormal triads, establishing a direct genotype–phenotype relationship.\",\n      \"evidence\": \"Exome/genome sequencing in four unrelated families, electron microscopy of muscle biopsies showing reduced triads and abnormal SR, RNA-seq expression outlier analysis\",\n      \"pmids\": [\"39209426\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No rescue or reconstitution experiment has been performed to confirm causality beyond genetic association\",\n        \"Calcium handling defects in patient muscle have not been directly measured\",\n        \"Whether residual JPH2 partially compensates in JPH1-null muscle is unknown\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extending the conserved role of junctophilin-1 in muscle physiology to an invertebrate model: knockdown of the C. elegans ortholog jph-1 impaired muscle endurance and altered nervous system morphology, supporting an evolutionarily conserved function in muscle calcium signaling.\",\n      \"evidence\": \"RNAi-mediated knockdown in C. elegans with locomotion (thrashing) and morphological assays\",\n      \"pmids\": [\"39381635\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-organism, single-lab study without independent replication\",\n        \"Molecular mechanism of jph-1 function in C. elegans muscle has not been dissected\",\n        \"Whether the nervous system morphology phenotype reflects a direct neuronal role or secondary effects is unclear\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the high-resolution structure of the JPH1–RyR1 complex, the physiological significance of redox-dependent modulation of this interaction for calcium release, and whether JPH1 has functions beyond triad tethering (e.g., signaling or transcriptional roles reported for other junctophilins).\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of the JPH1–RyR1 complex exists\",\n        \"In vivo functional consequence of cysteine redox modification on EC coupling has not been tested\",\n        \"Animal knockout models with detailed physiological characterization are lacking\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-397014\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"RYR1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"JPH1 (junctophilin-1) is a structural membrane-tethering protein that physically bridges the sarcoplasmic reticulum (SR) and T-tubule plasma membrane to form junctional membrane complexes essential for excitation–contraction (EC) coupling in skeletal muscle [PMID:10949023]. Its C-terminal hydrophobic segment anchors in the SR membrane while its cytoplasmic domain binds the T-tubule; this domain also directly interacts with the RyR1 Ca²⁺-release channel in a conformation- and redox-sensitive manner through hyper-reactive cysteine residues (Cys101, Cys402, Cys627) [PMID:17237236]. JPH1 is subject to Ca²⁺-dependent proteolysis by µ-calpain near its C-terminus, which disrupts EC coupling and is observed in dystrophic muscle [PMID:23148318]. Homozygous loss-of-function variants in JPH1 cause congenital myopathy with defective triad junction formation in humans [PMID:39209426].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"The identification of junctophilins as a protein family established that a dedicated structural molecule tethers the SR to T-tubules, answering how junctional membrane complexes critical for EC coupling are physically maintained.\",\n      \"evidence\": \"Molecular cloning, subcellular fractionation, and JP-2-null mouse analysis demonstrating loss of junctional membrane complexes\",\n      \"pmids\": [\"10949023\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No direct JPH1 knockout phenotype characterized at this stage\",\n        \"Identity of JPH1's channel interaction partners unknown\",\n        \"Mechanism of plasma membrane binding by the cytoplasmic domain unresolved\"\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrating a direct, conformation-sensitive JPH1–RyR1 interaction with redox-sensitive cysteines revealed that JPH1 is not merely a passive tether but an integral component of the Ca²⁺-release channel complex capable of sensing oxidative stress.\",\n      \"evidence\": \"Co-immunoprecipitation and mass spectrometry–based cysteine mapping with thiol-reactive probes in skeletal muscle preparations\",\n      \"pmids\": [\"17237236\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Functional consequences of cysteine oxidation on EC coupling not directly measured\",\n        \"No structural model of the JPH1–RyR1 interface\",\n        \"Whether redox modification of JPH1 occurs in vivo under physiological or pathological conditions was not tested\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identification of µ-calpain–mediated proteolysis of JPH1 at pathological Ca²⁺ levels, coincident with loss of depolarization-induced force, established a molecular mechanism by which Ca²⁺ overload dismantles the triad junction and disables EC coupling.\",\n      \"evidence\": \"Biochemical fractionation at defined [Ca²⁺], skinned fibre force measurements, in vitro stimulation, and immunoblotting in wild-type and mdx mouse muscle\",\n      \"pmids\": [\"23148318\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Exact calpain cleavage site(s) in JPH1 not mapped at residue resolution\",\n        \"Whether the released ~75 kDa fragment has any signaling role (as reported for JPH2 N-terminal fragments) is unknown\",\n        \"Contribution of JPH1 proteolysis versus other calpain substrates to EC coupling failure not dissected\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Discovery of biallelic JPH1 loss-of-function variants causing human congenital myopathy with triad abnormalities demonstrated that JPH1 is non-redundant with JPH2 in skeletal muscle and is required for normal triad formation in humans.\",\n      \"evidence\": \"Exome/genome sequencing in four unrelated families, RNA-seq expression outlier analysis, and electron microscopy of patient muscle biopsies\",\n      \"pmids\": [\"39209426\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single study; independent replication in additional cohorts not yet available\",\n        \"Genotype–phenotype correlations across different JPH1 variant types not established\",\n        \"Whether residual JPH2 partially compensates in affected patients is uncharacterized\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the atomic-resolution structure of JPH1 (alone and in complex with RyR1), the precise calpain cleavage site(s), the in vivo functional consequences of JPH1 cysteine oxidation, and whether the proteolytic N-terminal fragment has nuclear or signaling roles analogous to those described for JPH2.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No high-resolution structure of any junctophilin-1 domain or complex\",\n        \"Potential nuclear translocation of cleavage fragments untested for JPH1\",\n        \"Therapeutic strategies to prevent JPH1 proteolysis in dystrophic or overloaded muscle not explored\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-397014\", \"supporting_discovery_ids\": [0, 1, 2, 3]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"RYR1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}