{"gene":"KY","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":2001,"finding":"KY encodes a novel protein expressed exclusively in skeletal muscle and heart; loss of KY causes deficient hypertrophic response to mechanical demand and abnormal neuromuscular junction maturation/stabilization, establishing KY as essential for normal muscle growth and NMJ function.","method":"Positional cloning of ky locus, transcript analysis, histopathology of ky null mouse, functional muscle physiology assays","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — positional cloning with null mouse KO and defined cellular/physiological phenotypes, foundational discovery paper","pmids":["11136708"],"is_preprint":false},{"year":2004,"finding":"KY interacts with sarcomeric cytoskeletal proteins including filamin C (FLNC) and slow myosin-binding protein C; KY exhibits protease (transglutaminase-like peptidase) activity in vitro and specifically degrades filamin C in transfected cells; in ky null mouse muscle, filamin C shows irregular subcellular localization, indicating KY regulates filamin C proteolysis and distribution in vivo.","method":"Co-immunoprecipitation, in vitro protease assays, transfected cell degradation assay, immunofluorescence of ky null mouse muscle","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro enzymatic assay plus cell-based degradation assay plus in vivo localization, moderate-to-strong evidence from multiple orthogonal methods","pmids":["15385448"],"is_preprint":false},{"year":2010,"finding":"KY localizes to the Z-band in C2C12-derived myotubes and neonatal cardiomyocytes; KY forms a Z-band-associated protein complex with IGFN1 and FLNC, identified via yeast two-hybrid and biochemical interaction studies, providing structural support to the skeletal muscle sarcomere.","method":"Immunodetection of endogenous KY in myotubes, recombinant protein expression in cardiomyocytes, yeast two-hybrid screen, immunofluorescence co-localization","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 2 — direct subcellular localization with functional consequence tied to Z-band complex, multiple orthogonal methods (Y2H + biochemistry + imaging)","pmids":["20206623"],"is_preprint":false},{"year":2006,"finding":"In ky null mouse muscles, titin-based signaling proteins MLP, MARP2, and Xin are constitutively upregulated at the protein level as an early consequence of KY absence, linking KY function to titin structural/signaling stability and the stretch/stress response pathway.","method":"Protein expression analysis (Western blot/immunofluorescence) of ky/ky mouse muscles at multiple time points; comparison to titin mutant models and eccentric contraction paradigms","journal":"Neuromuscular disorders : NMD","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO with defined molecular phenotype, single lab but multiple protein targets and time points","pmids":["16806927"],"is_preprint":false},{"year":2004,"finding":"In dystrophic ky null soleus muscle, UCP1 is upregulated specifically at neuromuscular junctions with concurrent disorganization of acetylcholine receptor clusters and breakdown of MuSK-dependent NMJ signaling, placing KY in a pathway required for NMJ integrity.","method":"RNA profiling (microarray), protein-level validation by immunofluorescence, Western blot in ky null mouse muscle","journal":"Neuromuscular disorders : NMD","confidence":"Medium","confidence_rationale":"Tier 2 — RNA profiling validated at protein level in KO model with spatial/temporal localization data","pmids":["15036332"],"is_preprint":false},{"year":2018,"finding":"In ky-deficient C2C12 myotubes and ky null zebrafish (generated by CRISPR/Cas9), expression of BAG3 (a chaperone-assisted selective autophagy co-chaperone) and other CASA factors is elevated, and ky-deficient zebrafish fail to upregulate these factors under mechanical challenge; in ky/ky mouse soleus, BAG3 turnover is impaired. This places KY upstream of the CASA pathway that controls FLNC turnover.","method":"CRISPR/Cas9 KO in C2C12 cells and zebrafish, RT-qPCR and protein expression analysis, mechanical challenge assay (viscous media swimming)","journal":"Disease models & mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 — multiple model systems (cell, fish, mouse) with consistent molecular phenotype, single lab","pmids":["29914939"],"is_preprint":false},{"year":2016,"finding":"A homozygous loss-of-function variant in KY (c.1071delG, p.Thr358Leufs*3) causes early-onset neuromuscular disorder in humans with abnormal distribution of Xin and filamin C in muscle fibers, mirroring the altered localization seen in ky/ky mouse muscle and confirming the KY-FLNC regulatory interaction is conserved in humans.","method":"Whole-exome sequencing, muscle biopsy immunofluorescence for FLNC and Xin, RNA expression panel","journal":"European journal of human genetics : EJHG","confidence":"Medium","confidence_rationale":"Tier 2 — human loss-of-function with direct tissue-level localization phenotype confirming mechanistic interaction","pmids":["27485408"],"is_preprint":false},{"year":2002,"finding":"The C. elegans KY ortholog (ltd-1) encodes a protein with LIM and transglutaminase domains; LTD-1::GFP is expressed in hypodermal (epithelial) cells from embryo through adulthood, establishing the transglutaminase-like domain as an evolutionarily conserved feature of the KY protein family.","method":"GFP reporter construct expression in C. elegans, sequence domain analysis","journal":"Mechanisms of development","confidence":"Medium","confidence_rationale":"Tier 3 — ortholog characterization with direct localization imaging; domain architecture consistent with mammalian KY","pmids":["12204272"],"is_preprint":false},{"year":2012,"finding":"KY gene is downregulated in CAPN3 (calpain-3) knockout mouse muscles, suggesting KY protease acts downstream of or in parallel with calpain-3 in regulating muscle cytoskeleton homeostasis in response to changes in muscle activity.","method":"Gene expression profiling (microarray) of C3KO mouse muscles, validated at mRNA level","journal":"Neurogenetics","confidence":"Low","confidence_rationale":"Tier 3 — single expression profiling study; pathway placement is inferred, not directly tested","pmids":["22820870"],"is_preprint":false}],"current_model":"KY (kyphoscoliosis peptidase) is a muscle-specific transglutaminase-like protease that localizes to the sarcomeric Z-band, where it forms a complex with filamin C (FLNC) and IGFN1; it proteolytically regulates FLNC stability and subcellular distribution, acts upstream of the chaperone-assisted selective autophagy (CASA) pathway controlling FLNC turnover, and is required for neuromuscular junction integrity, the hypertrophic response to mechanical load, and titin-based stress signaling in skeletal muscle."},"narrative":{"teleology":[{"year":2001,"claim":"Positional cloning of the ky locus revealed that KY encodes a novel muscle-restricted protein whose absence causes failed hypertrophic adaptation to mechanical demand and neuromuscular junction abnormalities, establishing KY as essential for skeletal muscle growth and NMJ integrity.","evidence":"Positional cloning, transcript analysis, histopathology and functional physiology of ky null mice","pmids":["11136708"],"confidence":"High","gaps":["Molecular activity of KY protein unknown","Direct interacting partners not identified","Mechanism linking KY loss to NMJ disorganization unresolved"]},{"year":2002,"claim":"Characterization of the C. elegans ortholog (ltd-1) showed that the LIM and transglutaminase-like domain architecture of KY is evolutionarily conserved, suggesting an ancient functional role for this domain combination.","evidence":"GFP reporter expression and domain analysis in C. elegans","pmids":["12204272"],"confidence":"Medium","gaps":["Functional conservation beyond domain architecture not tested","No enzymatic activity demonstrated for LTD-1","Expression in hypodermal cells rather than muscle raises questions about tissue-specific roles across species"]},{"year":2004,"claim":"Two studies resolved KY's molecular function and its NMJ role: KY was shown to possess transglutaminase-like protease activity that degrades filamin C, and ky null muscle displayed disorganized acetylcholine receptor clusters with UCP1 upregulation at NMJs, linking KY to both cytoskeletal proteolysis and synaptic signaling integrity.","evidence":"Co-immunoprecipitation, in vitro protease assays, cell-based degradation assays, immunofluorescence and microarray profiling of ky null mouse muscle","pmids":["15385448","15036332"],"confidence":"High","gaps":["Catalytic mechanism and cleavage site on FLNC not defined","Whether KY protease activity is direct at the NMJ or acts indirectly through FLNC regulation unknown","MuSK pathway disruption not mechanistically dissected"]},{"year":2006,"claim":"Analysis of ky null muscle showed constitutive upregulation of titin-associated stress-signaling proteins MLP, MARP2, and Xin as an early consequence of KY loss, linking KY to the titin-based mechanosensory pathway at the Z-band.","evidence":"Western blot and immunofluorescence of ky/ky mouse muscles across developmental time points","pmids":["16806927"],"confidence":"Medium","gaps":["Whether KY directly modifies titin or titin-binding proteins not tested","Causal ordering between FLNC mislocalization and titin-signaling protein upregulation unclear","Single-lab observation without independent replication"]},{"year":2010,"claim":"KY was localized to the sarcomeric Z-band and shown to form a ternary complex with IGFN1 and FLNC, defining the structural context in which KY exerts its proteolytic function.","evidence":"Immunofluorescence in C2C12 myotubes and neonatal cardiomyocytes, yeast two-hybrid screen, co-localization analysis","pmids":["20206623"],"confidence":"High","gaps":["Stoichiometry and stability of the KY–IGFN1–FLNC complex not determined","Whether complex formation is required for protease activity unknown","No structural model of the complex available"]},{"year":2016,"claim":"A homozygous frameshift mutation in KY was identified as the cause of an early-onset human neuromuscular disorder, with FLNC and Xin mislocalization in patient muscle fibers mirroring the mouse phenotype, confirming KY's conserved role in sarcomeric protein regulation.","evidence":"Whole-exome sequencing, muscle biopsy immunofluorescence for FLNC and Xin","pmids":["27485408"],"confidence":"Medium","gaps":["Single family reported; additional kindreds needed to define clinical spectrum","Patient muscle not assessed for CASA pathway markers","Rescue experiment not performed"]},{"year":2018,"claim":"KY was placed upstream of the chaperone-assisted selective autophagy (CASA) pathway: ky-deficient cells, zebrafish, and mouse muscle showed elevated BAG3 and other CASA factors, and ky-null zebrafish failed to mount a CASA response to mechanical challenge, revealing how KY couples mechanotransduction to protein quality control.","evidence":"CRISPR/Cas9 KO in C2C12 cells and zebrafish, RT-qPCR, protein analysis, viscous media swimming challenge","pmids":["29914939"],"confidence":"Medium","gaps":["Direct mechanism by which KY regulates CASA factor expression or turnover not defined","Whether KY protease activity on FLNC is the upstream signal for CASA activation unknown","Single-lab observation across models but lacking biochemical reconstitution"]},{"year":null,"claim":"The catalytic mechanism and specific cleavage site(s) of KY on FLNC remain undefined, and it is unknown whether KY's protease activity is the direct signal that triggers CASA-mediated FLNC turnover or whether additional substrates exist.","evidence":"","pmids":[],"confidence":"High","gaps":["No crystal structure or cryo-EM model of KY","Substrate specificity beyond FLNC not explored","Mechanism linking KY protease activity to CASA pathway activation not biochemically reconstituted"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[1,2]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,5]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[5]}],"complexes":["KY–FLNC–IGFN1 Z-band complex"],"partners":["FLNC","IGFN1","MYBPC1","BAG3"],"other_free_text":[]},"mechanistic_narrative":"KY is a muscle-specific transglutaminase-like peptidase that localizes to the sarcomeric Z-band, where it forms a complex with filamin C (FLNC) and IGFN1 and proteolytically regulates FLNC stability and subcellular distribution [PMID:15385448, PMID:20206623]. Loss of KY in mouse, zebrafish, and human muscle leads to mislocalization of FLNC and Xin, constitutive upregulation of titin-associated stress-signaling proteins (MLP, MARP2, Xin), impaired chaperone-assisted selective autophagy (CASA)-mediated FLNC turnover, defective hypertrophic response to mechanical load, and neuromuscular junction disorganization [PMID:11136708, PMID:16806927, PMID:29914939, PMID:15036332]. Homozygous loss-of-function mutations in KY cause an early-onset human neuromuscular disorder with FLNC and Xin mislocalization in muscle fibers, confirming conservation of its sarcomeric regulatory function [PMID:27485408]."},"prefetch_data":{"uniprot":{"accession":"Q8NBH2","full_name":"Kyphoscoliosis peptidase","aliases":[],"length_aa":661,"mass_kda":75.2,"function":"Probable cytoskeleton-associated protease required for normal muscle growth. Involved in function, maturation and stabilization of the neuromuscular junction. May act by cleaving muscle-specific proteins such as FLNC (By similarity)","subcellular_location":"Cytoplasm, cytoskeleton; Cytoplasm, myofibril, sarcomere, Z line","url":"https://www.uniprot.org/uniprotkb/Q8NBH2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KY","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":[],"url":"https://opencell.sf.czbiohub.org/search/KY","total_profiled":1310},"omim":[{"mim_id":"621527","title":"TRANSMEMBRANE PROTEIN 145; TMEM145","url":"https://www.omim.org/entry/621527"},{"mim_id":"621314","title":"POMPE DISEASE, LATE-ONSET; LOPD","url":"https://www.omim.org/entry/621314"},{"mim_id":"620969","title":"ANEMIA, CONGENITAL DYSERYTHROPOIETIC, TYPE IVb; CDAN4B","url":"https://www.omim.org/entry/620969"},{"mim_id":"620777","title":"PULMONARY HYPERTENSION, PRIMARY, 6; PPH6","url":"https://www.omim.org/entry/620777"},{"mim_id":"620640","title":"RING FINGER PROTEIN 145; RNF145","url":"https://www.omim.org/entry/620640"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"skeletal muscle","ntpm":15.2},{"tissue":"tongue","ntpm":25.9}],"url":"https://www.proteinatlas.org/search/KY"},"hgnc":{"alias_symbol":["FLJ33207"],"prev_symbol":[]},"alphafold":{"accession":"Q8NBH2","domains":[{"cath_id":"3.10.620.30","chopping":"150-333","consensus_level":"high","plddt":92.0741,"start":150,"end":333},{"cath_id":"2.60.40.10","chopping":"346-436","consensus_level":"high","plddt":94.6598,"start":346,"end":436},{"cath_id":"2.60.40.10","chopping":"457-559","consensus_level":"high","plddt":90.5828,"start":457,"end":559},{"cath_id":"2.60.40.10","chopping":"571-659","consensus_level":"high","plddt":90.3416,"start":571,"end":659}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NBH2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NBH2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NBH2-F1-predicted_aligned_error_v6.png","plddt_mean":79.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KY","jax_strain_url":"https://www.jax.org/strain/search?query=KY"},"sequence":{"accession":"Q8NBH2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8NBH2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8NBH2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NBH2"}},"corpus_meta":[{"pmid":"11136708","id":"PMC_11136708","title":"The kyphoscoliosis (ky) mouse is deficient in hypertrophic responses and is caused by a mutation in a novel muscle-specific protein.","date":"2001","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11136708","citation_count":75,"is_preprint":false},{"pmid":"26657894","id":"PMC_26657894","title":"Ky-2, a Histone Deacetylase Inhibitor, Enhances High-Salinity Stress Tolerance in Arabidopsis thaliana.","date":"2015","source":"Plant & cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/26657894","citation_count":42,"is_preprint":false},{"pmid":"25337707","id":"PMC_25337707","title":"A novel aminothiazole KY-05009 with potential to inhibit Traf2- and Nck-interacting kinase (TNIK) attenuates TGF-β1-mediated epithelial-to-mesenchymal transition in human lung adenocarcinoma A549 cells.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25337707","citation_count":41,"is_preprint":false},{"pmid":"15385448","id":"PMC_15385448","title":"Filamin C interacts with the muscular dystrophy KY protein and is abnormally distributed in mouse KY deficient muscle fibres.","date":"2004","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15385448","citation_count":36,"is_preprint":false},{"pmid":"20206623","id":"PMC_20206623","title":"Identification of a Z-band associated protein complex involving KY, FLNC and IGFN1.","date":"2010","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/20206623","citation_count":30,"is_preprint":false},{"pmid":"7864091","id":"PMC_7864091","title":"Mechanical power and myosin composition of soleus and extensor digitorum longus muscles of ky mice.","date":"1995","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/7864091","citation_count":28,"is_preprint":false},{"pmid":"3928616","id":"PMC_3928616","title":"Extracellular tyrosinase from Streptomyces sp. 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European Food Safety Authority","url":"https://pubmed.ncbi.nlm.nih.gov/41246255","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":20476,"output_tokens":2159,"usd":0.046906},"stage2":{"model":"claude-opus-4-6","input_tokens":5446,"output_tokens":2159,"usd":0.121807},"total_usd":0.168713,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"KY encodes a novel protein expressed exclusively in skeletal muscle and heart; loss of KY causes deficient hypertrophic response to mechanical demand and abnormal neuromuscular junction maturation/stabilization, establishing KY as essential for normal muscle growth and NMJ function.\",\n      \"method\": \"Positional cloning of ky locus, transcript analysis, histopathology of ky null mouse, functional muscle physiology assays\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — positional cloning with null mouse KO and defined cellular/physiological phenotypes, foundational discovery paper\",\n      \"pmids\": [\"11136708\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"KY interacts with sarcomeric cytoskeletal proteins including filamin C (FLNC) and slow myosin-binding protein C; KY exhibits protease (transglutaminase-like peptidase) activity in vitro and specifically degrades filamin C in transfected cells; in ky null mouse muscle, filamin C shows irregular subcellular localization, indicating KY regulates filamin C proteolysis and distribution in vivo.\",\n      \"method\": \"Co-immunoprecipitation, in vitro protease assays, transfected cell degradation assay, immunofluorescence of ky null mouse muscle\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro enzymatic assay plus cell-based degradation assay plus in vivo localization, moderate-to-strong evidence from multiple orthogonal methods\",\n      \"pmids\": [\"15385448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"KY localizes to the Z-band in C2C12-derived myotubes and neonatal cardiomyocytes; KY forms a Z-band-associated protein complex with IGFN1 and FLNC, identified via yeast two-hybrid and biochemical interaction studies, providing structural support to the skeletal muscle sarcomere.\",\n      \"method\": \"Immunodetection of endogenous KY in myotubes, recombinant protein expression in cardiomyocytes, yeast two-hybrid screen, immunofluorescence co-localization\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct subcellular localization with functional consequence tied to Z-band complex, multiple orthogonal methods (Y2H + biochemistry + imaging)\",\n      \"pmids\": [\"20206623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"In ky null mouse muscles, titin-based signaling proteins MLP, MARP2, and Xin are constitutively upregulated at the protein level as an early consequence of KY absence, linking KY function to titin structural/signaling stability and the stretch/stress response pathway.\",\n      \"method\": \"Protein expression analysis (Western blot/immunofluorescence) of ky/ky mouse muscles at multiple time points; comparison to titin mutant models and eccentric contraction paradigms\",\n      \"journal\": \"Neuromuscular disorders : NMD\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined molecular phenotype, single lab but multiple protein targets and time points\",\n      \"pmids\": [\"16806927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"In dystrophic ky null soleus muscle, UCP1 is upregulated specifically at neuromuscular junctions with concurrent disorganization of acetylcholine receptor clusters and breakdown of MuSK-dependent NMJ signaling, placing KY in a pathway required for NMJ integrity.\",\n      \"method\": \"RNA profiling (microarray), protein-level validation by immunofluorescence, Western blot in ky null mouse muscle\",\n      \"journal\": \"Neuromuscular disorders : NMD\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RNA profiling validated at protein level in KO model with spatial/temporal localization data\",\n      \"pmids\": [\"15036332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In ky-deficient C2C12 myotubes and ky null zebrafish (generated by CRISPR/Cas9), expression of BAG3 (a chaperone-assisted selective autophagy co-chaperone) and other CASA factors is elevated, and ky-deficient zebrafish fail to upregulate these factors under mechanical challenge; in ky/ky mouse soleus, BAG3 turnover is impaired. This places KY upstream of the CASA pathway that controls FLNC turnover.\",\n      \"method\": \"CRISPR/Cas9 KO in C2C12 cells and zebrafish, RT-qPCR and protein expression analysis, mechanical challenge assay (viscous media swimming)\",\n      \"journal\": \"Disease models & mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple model systems (cell, fish, mouse) with consistent molecular phenotype, single lab\",\n      \"pmids\": [\"29914939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A homozygous loss-of-function variant in KY (c.1071delG, p.Thr358Leufs*3) causes early-onset neuromuscular disorder in humans with abnormal distribution of Xin and filamin C in muscle fibers, mirroring the altered localization seen in ky/ky mouse muscle and confirming the KY-FLNC regulatory interaction is conserved in humans.\",\n      \"method\": \"Whole-exome sequencing, muscle biopsy immunofluorescence for FLNC and Xin, RNA expression panel\",\n      \"journal\": \"European journal of human genetics : EJHG\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — human loss-of-function with direct tissue-level localization phenotype confirming mechanistic interaction\",\n      \"pmids\": [\"27485408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The C. elegans KY ortholog (ltd-1) encodes a protein with LIM and transglutaminase domains; LTD-1::GFP is expressed in hypodermal (epithelial) cells from embryo through adulthood, establishing the transglutaminase-like domain as an evolutionarily conserved feature of the KY protein family.\",\n      \"method\": \"GFP reporter construct expression in C. elegans, sequence domain analysis\",\n      \"journal\": \"Mechanisms of development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — ortholog characterization with direct localization imaging; domain architecture consistent with mammalian KY\",\n      \"pmids\": [\"12204272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"KY gene is downregulated in CAPN3 (calpain-3) knockout mouse muscles, suggesting KY protease acts downstream of or in parallel with calpain-3 in regulating muscle cytoskeleton homeostasis in response to changes in muscle activity.\",\n      \"method\": \"Gene expression profiling (microarray) of C3KO mouse muscles, validated at mRNA level\",\n      \"journal\": \"Neurogenetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single expression profiling study; pathway placement is inferred, not directly tested\",\n      \"pmids\": [\"22820870\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KY (kyphoscoliosis peptidase) is a muscle-specific transglutaminase-like protease that localizes to the sarcomeric Z-band, where it forms a complex with filamin C (FLNC) and IGFN1; it proteolytically regulates FLNC stability and subcellular distribution, acts upstream of the chaperone-assisted selective autophagy (CASA) pathway controlling FLNC turnover, and is required for neuromuscular junction integrity, the hypertrophic response to mechanical load, and titin-based stress signaling in skeletal muscle.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"KY is a muscle-specific transglutaminase-like peptidase that localizes to the sarcomeric Z-band, where it forms a complex with filamin C (FLNC) and IGFN1 and proteolytically regulates FLNC stability and subcellular distribution [PMID:15385448, PMID:20206623]. Loss of KY in mouse, zebrafish, and human muscle leads to mislocalization of FLNC and Xin, constitutive upregulation of titin-associated stress-signaling proteins (MLP, MARP2, Xin), impaired chaperone-assisted selective autophagy (CASA)-mediated FLNC turnover, defective hypertrophic response to mechanical load, and neuromuscular junction disorganization [PMID:11136708, PMID:16806927, PMID:29914939, PMID:15036332]. Homozygous loss-of-function mutations in KY cause an early-onset human neuromuscular disorder with FLNC and Xin mislocalization in muscle fibers, confirming conservation of its sarcomeric regulatory function [PMID:27485408].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Positional cloning of the ky locus revealed that KY encodes a novel muscle-restricted protein whose absence causes failed hypertrophic adaptation to mechanical demand and neuromuscular junction abnormalities, establishing KY as essential for skeletal muscle growth and NMJ integrity.\",\n      \"evidence\": \"Positional cloning, transcript analysis, histopathology and functional physiology of ky null mice\",\n      \"pmids\": [\"11136708\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular activity of KY protein unknown\",\n        \"Direct interacting partners not identified\",\n        \"Mechanism linking KY loss to NMJ disorganization unresolved\"\n      ]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Characterization of the C. elegans ortholog (ltd-1) showed that the LIM and transglutaminase-like domain architecture of KY is evolutionarily conserved, suggesting an ancient functional role for this domain combination.\",\n      \"evidence\": \"GFP reporter expression and domain analysis in C. elegans\",\n      \"pmids\": [\"12204272\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional conservation beyond domain architecture not tested\",\n        \"No enzymatic activity demonstrated for LTD-1\",\n        \"Expression in hypodermal cells rather than muscle raises questions about tissue-specific roles across species\"\n      ]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Two studies resolved KY's molecular function and its NMJ role: KY was shown to possess transglutaminase-like protease activity that degrades filamin C, and ky null muscle displayed disorganized acetylcholine receptor clusters with UCP1 upregulation at NMJs, linking KY to both cytoskeletal proteolysis and synaptic signaling integrity.\",\n      \"evidence\": \"Co-immunoprecipitation, in vitro protease assays, cell-based degradation assays, immunofluorescence and microarray profiling of ky null mouse muscle\",\n      \"pmids\": [\"15385448\", \"15036332\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Catalytic mechanism and cleavage site on FLNC not defined\",\n        \"Whether KY protease activity is direct at the NMJ or acts indirectly through FLNC regulation unknown\",\n        \"MuSK pathway disruption not mechanistically dissected\"\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Analysis of ky null muscle showed constitutive upregulation of titin-associated stress-signaling proteins MLP, MARP2, and Xin as an early consequence of KY loss, linking KY to the titin-based mechanosensory pathway at the Z-band.\",\n      \"evidence\": \"Western blot and immunofluorescence of ky/ky mouse muscles across developmental time points\",\n      \"pmids\": [\"16806927\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether KY directly modifies titin or titin-binding proteins not tested\",\n        \"Causal ordering between FLNC mislocalization and titin-signaling protein upregulation unclear\",\n        \"Single-lab observation without independent replication\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"KY was localized to the sarcomeric Z-band and shown to form a ternary complex with IGFN1 and FLNC, defining the structural context in which KY exerts its proteolytic function.\",\n      \"evidence\": \"Immunofluorescence in C2C12 myotubes and neonatal cardiomyocytes, yeast two-hybrid screen, co-localization analysis\",\n      \"pmids\": [\"20206623\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Stoichiometry and stability of the KY–IGFN1–FLNC complex not determined\",\n        \"Whether complex formation is required for protease activity unknown\",\n        \"No structural model of the complex available\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"A homozygous frameshift mutation in KY was identified as the cause of an early-onset human neuromuscular disorder, with FLNC and Xin mislocalization in patient muscle fibers mirroring the mouse phenotype, confirming KY's conserved role in sarcomeric protein regulation.\",\n      \"evidence\": \"Whole-exome sequencing, muscle biopsy immunofluorescence for FLNC and Xin\",\n      \"pmids\": [\"27485408\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single family reported; additional kindreds needed to define clinical spectrum\",\n        \"Patient muscle not assessed for CASA pathway markers\",\n        \"Rescue experiment not performed\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"KY was placed upstream of the chaperone-assisted selective autophagy (CASA) pathway: ky-deficient cells, zebrafish, and mouse muscle showed elevated BAG3 and other CASA factors, and ky-null zebrafish failed to mount a CASA response to mechanical challenge, revealing how KY couples mechanotransduction to protein quality control.\",\n      \"evidence\": \"CRISPR/Cas9 KO in C2C12 cells and zebrafish, RT-qPCR, protein analysis, viscous media swimming challenge\",\n      \"pmids\": [\"29914939\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct mechanism by which KY regulates CASA factor expression or turnover not defined\",\n        \"Whether KY protease activity on FLNC is the upstream signal for CASA activation unknown\",\n        \"Single-lab observation across models but lacking biochemical reconstitution\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The catalytic mechanism and specific cleavage site(s) of KY on FLNC remain undefined, and it is unknown whether KY's protease activity is the direct signal that triggers CASA-mediated FLNC turnover or whether additional substrates exist.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No crystal structure or cryo-EM model of KY\",\n        \"Substrate specificity beyond FLNC not explored\",\n        \"Mechanism linking KY protease activity to CASA pathway activation not biochemically reconstituted\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [\n      \"KY–FLNC–IGFN1 Z-band complex\"\n    ],\n    \"partners\": [\n      \"FLNC\",\n      \"IGFN1\",\n      \"MYBPC1\",\n      \"BAG3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}