{"gene":"KY","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2001,"finding":"The KY protein is encoded by a novel gene expressed exclusively in skeletal muscle and heart. Loss-of-function mutation in KY causes deficient muscle hypertrophy in response to increasing demand, while adaptive fibre type shifts still occur, and histopathology shows that KY is crucial for normal muscle growth, function, and maturation/stabilization of the neuromuscular junction.","method":"Positional cloning of the ky mouse mutant locus, expression analysis, histopathological characterization of null mutant muscles including neuromuscular junction analysis","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — positional cloning with multiple orthogonal methods (genetic mapping, expression analysis, histopathology, functional muscle assays), replicated across multiple muscle groups","pmids":["11136708"],"is_preprint":false},{"year":2004,"finding":"KY interacts with several sarcomeric cytoskeletal proteins including filamin C (FLNC) and the slow isoform of myosin-binding protein C. Interaction with FLNC was confirmed in vitro. KY shows protease activity in in vitro assays, and specific degradation of filamin C by KY was demonstrated in transfected cells. In KY-null mouse muscle fibres, filamin C shows distinct irregular subcellular localization, supporting a role for KY in regulating filamin C function in vivo.","method":"In vitro binding/pull-down assays, in vitro protease activity assays, transfected cell degradation assays, immunofluorescence of ky/ky null mouse muscle fibres","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro protease assay plus cell-based degradation plus in vivo localization phenotype, multiple orthogonal methods in a single focused study","pmids":["15385448"],"is_preprint":false},{"year":2010,"finding":"KY localizes to the Z-band in C2C12-derived myotubes and neonatal cardiomyocytes. KY interacts with IGFN1 (Immunoglobulin-like and fibronectin type 3 domain containing 1) and with the Z-band protein filamin C (FLNC) in a yeast two-hybrid screen. KY, IGFN1, and FLNC form a Z-band associated protein complex likely providing structural support to the skeletal muscle sarcomere.","method":"Immunodetection of endogenous KY in C2C12 myotubes, recombinant expression in neonatal cardiomyocytes, yeast two-hybrid screen, biochemical assays, immunofluorescence","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus biochemical interaction plus direct localization by immunofluorescence, multiple orthogonal methods in one study","pmids":["20206623"],"is_preprint":false},{"year":2006,"finding":"In KY-deficient muscles, titin-based signalling proteins MLP, MARP2, and Xin are constitutively upregulated at the protein level. This induction is an early consequence of KY absence and is also observed in muscles subjected to eccentric contractions and in specific titin mutants, suggesting that titin structural/signalling instability is a common feature of KY deficiency.","method":"Protein-level expression analysis (Western blot/immunodetection) in ky/ky mutant fast and slow muscles; comparison with other mouse muscle disease models","journal":"Neuromuscular disorders : NMD","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct protein-level characterization in null mutant, single lab, limited mechanistic follow-up","pmids":["16806927"],"is_preprint":false},{"year":2004,"finding":"Molecular profiling of ky/ky dystrophic soleus muscle revealed coordinated upregulation of uncoupling proteins 1 and 2 (UCP1 and UCP2) as a unique molecular signature. UCP1 upregulation was spatially and temporally associated with disorganisation of acetylcholine receptor clusters at the neuromuscular junction, suggesting disrupted NMJ signalling. Breakdown of muscle-specific kinase (MuSK)-dependent signalling was also evidenced in adult mutant soleus. Sarcolemma-associated proteins implicated in other muscular dystrophies were normally distributed.","method":"RNA profiling (microarray) of EDL and soleus muscles, immunofluorescence, protein expression validation","journal":"Neuromuscular disorders : NMD","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — microarray with immunofluorescence and protein validation, multiple methods in one study, single lab","pmids":["15036332"],"is_preprint":false},{"year":2002,"finding":"The C. elegans homologue of ky (named ltd-1) contains LIM and transglutaminase domains, and its LTD-1::GFP construct is expressed in developing hypodermal cells from the twofold stage embryo through adulthood, demonstrating the evolutionary conservation of the KY/LTD-1 protein family and indicating that the transglutaminase-like domain is an ancient conserved feature.","method":"Cloning of C. elegans ky homologue, GFP reporter construct expression analysis during development","journal":"Mechanisms of development","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct reporter localization in a model organism ortholog, single lab, GFP fusion approach; confirms transglutaminase-like domain conservation","pmids":["12204272"],"is_preprint":false},{"year":2012,"finding":"KY gene expression is downregulated in CAPN3 (calpain-3) knockout mouse muscles, suggesting that KY protease activity plays a complementary role in regulating muscle cytoskeleton homeostasis in response to changes in muscle activity.","method":"Gene expression profiling (microarray) of C3KO (CAPN3 knockout) mouse soleus muscle compared to wild-type","journal":"Neurogenetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — expression profiling only, single lab, no direct functional validation of the KY downregulation consequence","pmids":["22820870"],"is_preprint":false},{"year":2018,"finding":"In C2C12 myoblasts and zebrafish (ky-deficient models generated by CRISPR/Cas9), loss of KY leads to upregulation of BAG3 and other chaperone-assisted selective autophagy (CASA) factors (including flnca/b). Ky-deficient zebrafish challenged by swimming in viscous media cannot further increase expression of CASA factors unlike wild-type controls. In ky/ky mice, BAG3 is elevated in EDL and shows impaired turnover in pathological soleus, suggesting FLNC turnover via CASA is disrupted by KY deficiency.","method":"CRISPR/Cas9 knockout in C2C12 cells and zebrafish, gene expression analysis, swimming challenge assay, protein expression analysis in ky/ky mice","journal":"Disease models & mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR loss-of-function in two model systems with defined molecular readout plus mouse model confirmation, single lab","pmids":["29914939"],"is_preprint":false},{"year":2016,"finding":"Human loss-of-function mutation (homozygous c.1071delG, p.(Thr358Leufs*3)) in KY causes an early-onset neuromuscular disorder with nemaline rods and thickened Z-discs. Filamin C and Xin showed abnormal distribution in patient muscle fibres, highly similar to their altered localization in ky/ky mouse muscle fibres, confirming that KY deficiency disrupts the sarcomeric localization of filamin C in humans.","method":"Whole-exome sequencing identifying KY truncation; muscle biopsy with immunofluorescence showing mislocalization of FLNC and Xin","journal":"European journal of human genetics : EJHG","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human genetic loss-of-function with direct immunofluorescence confirmation of filamin C mislocalization, consistent with mouse model","pmids":["27485408"],"is_preprint":false},{"year":1998,"finding":"Positional cloning efforts mapped the ky locus to a region of mouse chromosome 9 contained within two overlapping BAC clones not exceeding 260 kb, and identified a candidate transcription unit expressed exclusively in skeletal muscle.","method":"YAC/BAC contig construction, STS content mapping, expression analysis of candidate transcription units","journal":"Genomics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — mapping and candidate gene identification without functional mechanistic data, single lab","pmids":["9878244"],"is_preprint":false}],"current_model":"KY (kyphoscoliosis peptidase) is a transglutaminase-like protease expressed specifically in skeletal muscle and heart that localizes to the sarcomeric Z-band as part of a complex with filamin C (FLNC) and IGFN1; it proteolytically processes filamin C in vitro and in cells, regulates filamin C subcellular localization in vivo, and its loss disrupts titin-based mechanosensing signalling, impairs neuromuscular junction stability and muscle hypertrophic responses, and triggers upregulation of the chaperone-assisted selective autophagy pathway, collectively explaining why KY-null mice develop postural muscle dystrophy and kyphoscoliosis, and why human loss-of-function mutations cause myofibrillar myopathy and/or hereditary spastic paraplegia."},"narrative":{"mechanistic_narrative":"KY encodes a transglutaminase-like protease expressed specifically in skeletal muscle and heart that is essential for normal muscle growth, function, and maturation of the neuromuscular junction, with its loss producing a postural muscle dystrophy [PMID:11136708]. KY localizes to the sarcomeric Z-band, where it assembles with IGFN1 and filamin C (FLNC) into a Z-band-associated complex that provides structural support to the sarcomere [PMID:20206623]. Mechanistically, KY exhibits intrinsic protease activity, binds FLNC, and proteolytically degrades filamin C in cells, and its loss in vivo produces irregular FLNC subcellular distribution, establishing KY as a regulator of filamin C localization and turnover [PMID:15385448]. Consistent with a sarcomeric maintenance role, KY deficiency triggers constitutive upregulation of titin-based signalling proteins (MLP, MARP2, Xin), pointing to titin structural/signalling instability as an early consequence of KY loss [PMID:16806927], and drives upregulation of BAG3 and other chaperone-assisted selective autophagy factors with impaired turnover, indicating that FLNC clearance via CASA is dysregulated when KY is absent [PMID:29914939]. In humans, biallelic loss-of-function mutation in KY causes an early-onset neuromuscular disorder with nemaline rods and thickened Z-discs, accompanied by abnormal FLNC and Xin distribution that mirrors the mouse phenotype [PMID:27485408].","teleology":[{"year":1998,"claim":"Before KY had a molecular identity, the ky mouse mutant locus needed to be cloned; mapping localized the gene to a small chromosome 9 interval and pinpointed a muscle-specific candidate transcription unit.","evidence":"YAC/BAC contig construction and STS mapping with expression screening in mouse","pmids":["9878244"],"confidence":"Low","gaps":["No functional or mechanistic data on the candidate gene","Protein product and activity unknown at this stage"]},{"year":2001,"claim":"Positional cloning identified KY as a novel muscle- and heart-specific gene and established that its loss impairs hypertrophic muscle growth and neuromuscular junction maturation, defining its physiological importance.","evidence":"Positional cloning, expression analysis, and histopathology of ky/ky null muscle including NMJ analysis","pmids":["11136708"],"confidence":"High","gaps":["Molecular activity of the KY protein not yet determined","Direct binding partners and substrates unidentified"]},{"year":2002,"claim":"Identification of the C. elegans homologue ltd-1 with LIM and transglutaminase domains established that the transglutaminase-like domain is an evolutionarily ancient, conserved feature of the protein family.","evidence":"Cloning of the C. elegans ortholog and GFP reporter expression during development","pmids":["12204272"],"confidence":"Medium","gaps":["Catalytic activity of the conserved domain not demonstrated in this work","Functional relationship of hypodermal expression to mammalian muscle role unclear"]},{"year":2004,"claim":"To define KY's biochemical function, interaction and activity assays showed KY binds filamin C, has protease activity, degrades filamin C in cells, and that FLNC is mislocalized in KY-null muscle, establishing KY as a protease regulating filamin C.","evidence":"In vitro binding/pull-down, in vitro protease assays, transfected-cell degradation assays, and immunofluorescence of ky/ky muscle","pmids":["15385448"],"confidence":"High","gaps":["Endogenous physiological substrates beyond filamin C not enumerated","Catalytic residues and cleavage site not mapped"]},{"year":2004,"claim":"Molecular profiling of dystrophic ky/ky soleus revealed a UCP1/UCP2 signature linked spatially to disorganized acetylcholine receptor clusters and disrupted MuSK-dependent signalling, connecting KY loss to NMJ signalling breakdown.","evidence":"Microarray profiling of EDL and soleus with immunofluorescence and protein validation","pmids":["15036332"],"confidence":"Medium","gaps":["Causal link between KY protease activity and NMJ/UCP changes not established","Whether UCP upregulation is primary or secondary unresolved"]},{"year":2006,"claim":"Examining downstream signalling showed titin-based proteins MLP, MARP2, and Xin are constitutively upregulated in KY-deficient muscle, implicating titin structural/signalling instability as an early consequence of KY loss.","evidence":"Protein-level expression analysis in ky/ky fast and slow muscles with comparison to other disease models","pmids":["16806927"],"confidence":"Medium","gaps":["Direct mechanistic link between KY and titin signalling not shown","Single-lab characterization without functional rescue"]},{"year":2010,"claim":"Localization and interaction studies placed KY at the Z-band in a complex with IGFN1 and FLNC, defining a structural sarcomeric module rather than a purely catalytic role.","evidence":"Endogenous immunodetection in C2C12 myotubes, expression in cardiomyocytes, yeast two-hybrid, biochemistry, and immunofluorescence","pmids":["20206623"],"confidence":"High","gaps":["Stoichiometry and assembly order of the KY–IGFN1–FLNC complex unknown","Whether IGFN1 is a substrate or scaffold not resolved"]},{"year":2012,"claim":"Expression profiling of CAPN3-knockout muscle found KY downregulated, hinting at a complementary role for KY protease activity in cytoskeleton homeostasis during changes in muscle activity.","evidence":"Microarray of C3KO soleus versus wild-type","pmids":["22820870"],"confidence":"Low","gaps":["Expression correlation only, no functional validation of consequence","Direct CAPN3–KY mechanistic interaction not tested"]},{"year":2016,"claim":"A homozygous KY truncation in patients with an early-onset neuromuscular disorder showing nemaline rods, thickened Z-discs, and FLNC/Xin mislocalization translated the mouse mechanism to human disease.","evidence":"Whole-exome sequencing and muscle biopsy immunofluorescence","pmids":["27485408"],"confidence":"Medium","gaps":["Genotype–phenotype range across patients not defined","Residual protease function of the truncation not assessed"]},{"year":2018,"claim":"CRISPR loss-of-function in C2C12 cells and zebrafish, plus mouse data, showed KY deficiency upregulates BAG3 and CASA factors and impairs their stress-induced adaptation, linking KY to chaperone-assisted selective autophagy-mediated FLNC turnover.","evidence":"CRISPR/Cas9 knockout in cells and zebrafish, swimming-challenge assay, and protein analysis in ky/ky mice","pmids":["29914939"],"confidence":"Medium","gaps":["Direct molecular link between KY protease activity and CASA induction unresolved","Whether CASA upregulation compensates for or contributes to pathology unclear"]},{"year":null,"claim":"How KY protease activity is regulated and how its cleavage of filamin C is mechanistically coupled to titin signalling, NMJ stability, and CASA induction remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the KY catalytic domain or cleavage mechanism","Catalytic residues and physiological substrate repertoire incompletely defined","Direct mechanistic chain from KY loss to titin/CASA/NMJ phenotypes not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[7]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1]}],"complexes":["KY–IGFN1–FLNC Z-band complex"],"partners":["FLNC","IGFN1"],"other_free_text":[]}},"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":"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. KY-453: purification and some enzymatic properties.","date":"1985","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/3928616","citation_count":27,"is_preprint":false},{"pmid":"30579831","id":"PMC_30579831","title":"KY-226 Protects Blood-brain Barrier Function Through the Akt/FoxO1 Signaling Pathway in Brain Ischemia.","date":"2018","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/30579831","citation_count":24,"is_preprint":false},{"pmid":"28892347","id":"PMC_28892347","title":"Two Cooperative Glycosyltransferases Are Responsible for the Sugar Diversity of Saquayamycins Isolated from Streptomyces sp. KY 40-1.","date":"2017","source":"ACS chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/28892347","citation_count":22,"is_preprint":false},{"pmid":"14659539","id":"PMC_14659539","title":"Purification and characterization of an aldehyde oxidase from Pseudomonas sp. KY 4690.","date":"2003","source":"FEMS microbiology letters","url":"https://pubmed.ncbi.nlm.nih.gov/14659539","citation_count":21,"is_preprint":false},{"pmid":"28467797","id":"PMC_28467797","title":"Synergistic inhibition effect of TNIK inhibitor KY-05009 and receptor tyrosine kinase inhibitor dovitinib on IL-6-induced proliferation and Wnt signaling pathway in human multiple myeloma cells.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/28467797","citation_count":19,"is_preprint":false},{"pmid":"7874009","id":"PMC_7874009","title":"Low expression of the deoxycytidine kinase (dCK) gene in a 1-beta-D-arabinofuranosylcytosine-resistant human leukemic cell line KY-Ra.","date":"1994","source":"Leukemia & lymphoma","url":"https://pubmed.ncbi.nlm.nih.gov/7874009","citation_count":19,"is_preprint":false},{"pmid":"28488683","id":"PMC_28488683","title":"Progressive hereditary spastic paraplegia caused by a homozygous KY mutation.","date":"2017","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/28488683","citation_count":17,"is_preprint":false},{"pmid":"27485408","id":"PMC_27485408","title":"A new early-onset neuromuscular disorder associated with kyphoscoliosis peptidase (KY) deficiency.","date":"2016","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/27485408","citation_count":15,"is_preprint":false},{"pmid":"29731242","id":"PMC_29731242","title":"Therapeutic effects of the allosteric protein tyrosine phosphatase 1B inhibitor KY-226 on experimental diabetes and obesity via enhancements in insulin and leptin signaling in mice.","date":"2018","source":"Journal of pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/29731242","citation_count":14,"is_preprint":false},{"pmid":"8944783","id":"PMC_8944783","title":"Isoforms of myosin in growing muscles of ky (kyphoscoliotic) mice.","date":"1996","source":"European journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8944783","citation_count":14,"is_preprint":false},{"pmid":"17546199","id":"PMC_17546199","title":"Microjoule pulses from a passively mode-locked Yb:KY(WO(4))(2) thin-disk oscillator with cavity dumping.","date":"2007","source":"Optics letters","url":"https://pubmed.ncbi.nlm.nih.gov/17546199","citation_count":14,"is_preprint":false},{"pmid":"16806927","id":"PMC_16806927","title":"Constitutive upregulations of titin-based signalling proteins in KY deficient muscles.","date":"2006","source":"Neuromuscular disorders : NMD","url":"https://pubmed.ncbi.nlm.nih.gov/16806927","citation_count":12,"is_preprint":false},{"pmid":"33225177","id":"PMC_33225177","title":"Characterization and Application of a Recombinant Exolytic GH50A β-Agarase from Cellvibrio sp. KY-GH-1 for Enzymatic Production of Neoagarobiose from Agarose.","date":"2020","source":"ACS omega","url":"https://pubmed.ncbi.nlm.nih.gov/33225177","citation_count":10,"is_preprint":false},{"pmid":"30238554","id":"PMC_30238554","title":"Ky-2, a hybrid compound histone deacetylase inhibitor, regulated inflammatory response in LPS-driven human macrophages.","date":"2018","source":"Cell biology international","url":"https://pubmed.ncbi.nlm.nih.gov/30238554","citation_count":9,"is_preprint":false},{"pmid":"38508765","id":"PMC_38508765","title":"Osteoblastgenic and Osteogenic Effects of KY-273 with CDK8/19 Inhibitory Activity in Bone Marrow Mesenchymal Stem Cells and Female Rats.","date":"2024","source":"Biological & pharmaceutical bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/38508765","citation_count":8,"is_preprint":false},{"pmid":"12204272","id":"PMC_12204272","title":"Cloning and developmental expression analysis of ltd-1, the Caenorhabditis elegans homologue of the mouse kyphoscoliosis (ky) gene.","date":"2002","source":"Mechanisms of development","url":"https://pubmed.ncbi.nlm.nih.gov/12204272","citation_count":8,"is_preprint":false},{"pmid":"7934146","id":"PMC_7934146","title":"Characterization of newly established adriamycin resistant human leukemic cell lines (KY-ADR1 and KY-ADR2).","date":"1994","source":"Leukemia research","url":"https://pubmed.ncbi.nlm.nih.gov/7934146","citation_count":7,"is_preprint":false},{"pmid":"22820870","id":"PMC_22820870","title":"C3KO mouse expression analysis: downregulation of the muscular dystrophy Ky protein and alterations in muscle aging.","date":"2012","source":"Neurogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/22820870","citation_count":6,"is_preprint":false},{"pmid":"15036332","id":"PMC_15036332","title":"Molecular phenotyping of the mouse ky mutant reveals UCP1 upregulation at the neuromuscular junctions of dystrophic soleus muscle.","date":"2004","source":"Neuromuscular disorders : NMD","url":"https://pubmed.ncbi.nlm.nih.gov/15036332","citation_count":6,"is_preprint":false},{"pmid":"31193527","id":"PMC_31193527","title":"Whole genome sequence of a freshwater agar-degrading bacterium Cellvibrio sp. 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Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/39674288","citation_count":1,"is_preprint":false},{"pmid":"18479017","id":"PMC_18479017","title":"[Study on crystal growth and vibrational spectra of Yb(x) : KY(1-x) (WO4)2].","date":"2008","source":"Guang pu xue yu guang pu fen xi = Guang pu","url":"https://pubmed.ncbi.nlm.nih.gov/18479017","citation_count":0,"is_preprint":false},{"pmid":"41246255","id":"PMC_41246255","title":"Safety evaluation of the food enzyme α-amylase from the non-genetically modified Bacillus licheniformis strain TTME 6280 KY.","date":"2025","source":"EFSA journal. 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":20242,"output_tokens":2731,"usd":0.050846,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9982,"output_tokens":3244,"usd":0.065505,"stage2_stop_reason":"end_turn"},"total_usd":0.116351,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"The KY protein is encoded by a novel gene expressed exclusively in skeletal muscle and heart. Loss-of-function mutation in KY causes deficient muscle hypertrophy in response to increasing demand, while adaptive fibre type shifts still occur, and histopathology shows that KY is crucial for normal muscle growth, function, and maturation/stabilization of the neuromuscular junction.\",\n      \"method\": \"Positional cloning of the ky mouse mutant locus, expression analysis, histopathological characterization of null mutant muscles including neuromuscular junction analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — positional cloning with multiple orthogonal methods (genetic mapping, expression analysis, histopathology, functional muscle assays), replicated across multiple muscle groups\",\n      \"pmids\": [\"11136708\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"KY interacts with several sarcomeric cytoskeletal proteins including filamin C (FLNC) and the slow isoform of myosin-binding protein C. Interaction with FLNC was confirmed in vitro. KY shows protease activity in in vitro assays, and specific degradation of filamin C by KY was demonstrated in transfected cells. In KY-null mouse muscle fibres, filamin C shows distinct irregular subcellular localization, supporting a role for KY in regulating filamin C function in vivo.\",\n      \"method\": \"In vitro binding/pull-down assays, in vitro protease activity assays, transfected cell degradation assays, immunofluorescence of ky/ky null mouse muscle fibres\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro protease assay plus cell-based degradation plus in vivo localization phenotype, multiple orthogonal methods in a single focused study\",\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 interacts with IGFN1 (Immunoglobulin-like and fibronectin type 3 domain containing 1) and with the Z-band protein filamin C (FLNC) in a yeast two-hybrid screen. KY, IGFN1, and FLNC form a Z-band associated protein complex likely providing structural support to the skeletal muscle sarcomere.\",\n      \"method\": \"Immunodetection of endogenous KY in C2C12 myotubes, recombinant expression in neonatal cardiomyocytes, yeast two-hybrid screen, biochemical assays, immunofluorescence\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus biochemical interaction plus direct localization by immunofluorescence, multiple orthogonal methods in one study\",\n      \"pmids\": [\"20206623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"In KY-deficient muscles, titin-based signalling proteins MLP, MARP2, and Xin are constitutively upregulated at the protein level. This induction is an early consequence of KY absence and is also observed in muscles subjected to eccentric contractions and in specific titin mutants, suggesting that titin structural/signalling instability is a common feature of KY deficiency.\",\n      \"method\": \"Protein-level expression analysis (Western blot/immunodetection) in ky/ky mutant fast and slow muscles; comparison with other mouse muscle disease models\",\n      \"journal\": \"Neuromuscular disorders : NMD\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct protein-level characterization in null mutant, single lab, limited mechanistic follow-up\",\n      \"pmids\": [\"16806927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Molecular profiling of ky/ky dystrophic soleus muscle revealed coordinated upregulation of uncoupling proteins 1 and 2 (UCP1 and UCP2) as a unique molecular signature. UCP1 upregulation was spatially and temporally associated with disorganisation of acetylcholine receptor clusters at the neuromuscular junction, suggesting disrupted NMJ signalling. Breakdown of muscle-specific kinase (MuSK)-dependent signalling was also evidenced in adult mutant soleus. Sarcolemma-associated proteins implicated in other muscular dystrophies were normally distributed.\",\n      \"method\": \"RNA profiling (microarray) of EDL and soleus muscles, immunofluorescence, protein expression validation\",\n      \"journal\": \"Neuromuscular disorders : NMD\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — microarray with immunofluorescence and protein validation, multiple methods in one study, single lab\",\n      \"pmids\": [\"15036332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The C. elegans homologue of ky (named ltd-1) contains LIM and transglutaminase domains, and its LTD-1::GFP construct is expressed in developing hypodermal cells from the twofold stage embryo through adulthood, demonstrating the evolutionary conservation of the KY/LTD-1 protein family and indicating that the transglutaminase-like domain is an ancient conserved feature.\",\n      \"method\": \"Cloning of C. elegans ky homologue, GFP reporter construct expression analysis during development\",\n      \"journal\": \"Mechanisms of development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct reporter localization in a model organism ortholog, single lab, GFP fusion approach; confirms transglutaminase-like domain conservation\",\n      \"pmids\": [\"12204272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"KY gene expression is downregulated in CAPN3 (calpain-3) knockout mouse muscles, suggesting that KY protease activity plays a complementary role in regulating muscle cytoskeleton homeostasis in response to changes in muscle activity.\",\n      \"method\": \"Gene expression profiling (microarray) of C3KO (CAPN3 knockout) mouse soleus muscle compared to wild-type\",\n      \"journal\": \"Neurogenetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — expression profiling only, single lab, no direct functional validation of the KY downregulation consequence\",\n      \"pmids\": [\"22820870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In C2C12 myoblasts and zebrafish (ky-deficient models generated by CRISPR/Cas9), loss of KY leads to upregulation of BAG3 and other chaperone-assisted selective autophagy (CASA) factors (including flnca/b). Ky-deficient zebrafish challenged by swimming in viscous media cannot further increase expression of CASA factors unlike wild-type controls. In ky/ky mice, BAG3 is elevated in EDL and shows impaired turnover in pathological soleus, suggesting FLNC turnover via CASA is disrupted by KY deficiency.\",\n      \"method\": \"CRISPR/Cas9 knockout in C2C12 cells and zebrafish, gene expression analysis, swimming challenge assay, protein expression analysis in ky/ky mice\",\n      \"journal\": \"Disease models & mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR loss-of-function in two model systems with defined molecular readout plus mouse model confirmation, single lab\",\n      \"pmids\": [\"29914939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Human loss-of-function mutation (homozygous c.1071delG, p.(Thr358Leufs*3)) in KY causes an early-onset neuromuscular disorder with nemaline rods and thickened Z-discs. Filamin C and Xin showed abnormal distribution in patient muscle fibres, highly similar to their altered localization in ky/ky mouse muscle fibres, confirming that KY deficiency disrupts the sarcomeric localization of filamin C in humans.\",\n      \"method\": \"Whole-exome sequencing identifying KY truncation; muscle biopsy with immunofluorescence showing mislocalization of FLNC and Xin\",\n      \"journal\": \"European journal of human genetics : EJHG\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human genetic loss-of-function with direct immunofluorescence confirmation of filamin C mislocalization, consistent with mouse model\",\n      \"pmids\": [\"27485408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Positional cloning efforts mapped the ky locus to a region of mouse chromosome 9 contained within two overlapping BAC clones not exceeding 260 kb, and identified a candidate transcription unit expressed exclusively in skeletal muscle.\",\n      \"method\": \"YAC/BAC contig construction, STS content mapping, expression analysis of candidate transcription units\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — mapping and candidate gene identification without functional mechanistic data, single lab\",\n      \"pmids\": [\"9878244\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KY (kyphoscoliosis peptidase) is a transglutaminase-like protease expressed specifically in skeletal muscle and heart that localizes to the sarcomeric Z-band as part of a complex with filamin C (FLNC) and IGFN1; it proteolytically processes filamin C in vitro and in cells, regulates filamin C subcellular localization in vivo, and its loss disrupts titin-based mechanosensing signalling, impairs neuromuscular junction stability and muscle hypertrophic responses, and triggers upregulation of the chaperone-assisted selective autophagy pathway, collectively explaining why KY-null mice develop postural muscle dystrophy and kyphoscoliosis, and why human loss-of-function mutations cause myofibrillar myopathy and/or hereditary spastic paraplegia.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KY encodes a transglutaminase-like protease expressed specifically in skeletal muscle and heart that is essential for normal muscle growth, function, and maturation of the neuromuscular junction, with its loss producing a postural muscle dystrophy [#0]. KY localizes to the sarcomeric Z-band, where it assembles with IGFN1 and filamin C (FLNC) into a Z-band-associated complex that provides structural support to the sarcomere [#2]. Mechanistically, KY exhibits intrinsic protease activity, binds FLNC, and proteolytically degrades filamin C in cells, and its loss in vivo produces irregular FLNC subcellular distribution, establishing KY as a regulator of filamin C localization and turnover [#1]. Consistent with a sarcomeric maintenance role, KY deficiency triggers constitutive upregulation of titin-based signalling proteins (MLP, MARP2, Xin), pointing to titin structural/signalling instability as an early consequence of KY loss [#3], and drives upregulation of BAG3 and other chaperone-assisted selective autophagy factors with impaired turnover, indicating that FLNC clearance via CASA is dysregulated when KY is absent [#7]. In humans, biallelic loss-of-function mutation in KY causes an early-onset neuromuscular disorder with nemaline rods and thickened Z-discs, accompanied by abnormal FLNC and Xin distribution that mirrors the mouse phenotype [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Before KY had a molecular identity, the ky mouse mutant locus needed to be cloned; mapping localized the gene to a small chromosome 9 interval and pinpointed a muscle-specific candidate transcription unit.\",\n      \"evidence\": \"YAC/BAC contig construction and STS mapping with expression screening in mouse\",\n      \"pmids\": [\"9878244\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No functional or mechanistic data on the candidate gene\", \"Protein product and activity unknown at this stage\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Positional cloning identified KY as a novel muscle- and heart-specific gene and established that its loss impairs hypertrophic muscle growth and neuromuscular junction maturation, defining its physiological importance.\",\n      \"evidence\": \"Positional cloning, expression analysis, and histopathology of ky/ky null muscle including NMJ analysis\",\n      \"pmids\": [\"11136708\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular activity of the KY protein not yet determined\", \"Direct binding partners and substrates unidentified\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identification of the C. elegans homologue ltd-1 with LIM and transglutaminase domains established that the transglutaminase-like domain is an evolutionarily ancient, conserved feature of the protein family.\",\n      \"evidence\": \"Cloning of the C. elegans ortholog and GFP reporter expression during development\",\n      \"pmids\": [\"12204272\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Catalytic activity of the conserved domain not demonstrated in this work\", \"Functional relationship of hypodermal expression to mammalian muscle role unclear\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"To define KY's biochemical function, interaction and activity assays showed KY binds filamin C, has protease activity, degrades filamin C in cells, and that FLNC is mislocalized in KY-null muscle, establishing KY as a protease regulating filamin C.\",\n      \"evidence\": \"In vitro binding/pull-down, in vitro protease assays, transfected-cell degradation assays, and immunofluorescence of ky/ky muscle\",\n      \"pmids\": [\"15385448\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous physiological substrates beyond filamin C not enumerated\", \"Catalytic residues and cleavage site not mapped\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Molecular profiling of dystrophic ky/ky soleus revealed a UCP1/UCP2 signature linked spatially to disorganized acetylcholine receptor clusters and disrupted MuSK-dependent signalling, connecting KY loss to NMJ signalling breakdown.\",\n      \"evidence\": \"Microarray profiling of EDL and soleus with immunofluorescence and protein validation\",\n      \"pmids\": [\"15036332\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal link between KY protease activity and NMJ/UCP changes not established\", \"Whether UCP upregulation is primary or secondary unresolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Examining downstream signalling showed titin-based proteins MLP, MARP2, and Xin are constitutively upregulated in KY-deficient muscle, implicating titin structural/signalling instability as an early consequence of KY loss.\",\n      \"evidence\": \"Protein-level expression analysis in ky/ky fast and slow muscles with comparison to other disease models\",\n      \"pmids\": [\"16806927\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mechanistic link between KY and titin signalling not shown\", \"Single-lab characterization without functional rescue\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Localization and interaction studies placed KY at the Z-band in a complex with IGFN1 and FLNC, defining a structural sarcomeric module rather than a purely catalytic role.\",\n      \"evidence\": \"Endogenous immunodetection in C2C12 myotubes, expression in cardiomyocytes, yeast two-hybrid, biochemistry, and immunofluorescence\",\n      \"pmids\": [\"20206623\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and assembly order of the KY–IGFN1–FLNC complex unknown\", \"Whether IGFN1 is a substrate or scaffold not resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Expression profiling of CAPN3-knockout muscle found KY downregulated, hinting at a complementary role for KY protease activity in cytoskeleton homeostasis during changes in muscle activity.\",\n      \"evidence\": \"Microarray of C3KO soleus versus wild-type\",\n      \"pmids\": [\"22820870\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Expression correlation only, no functional validation of consequence\", \"Direct CAPN3–KY mechanistic interaction not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"A homozygous KY truncation in patients with an early-onset neuromuscular disorder showing nemaline rods, thickened Z-discs, and FLNC/Xin mislocalization translated the mouse mechanism to human disease.\",\n      \"evidence\": \"Whole-exome sequencing and muscle biopsy immunofluorescence\",\n      \"pmids\": [\"27485408\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Genotype–phenotype range across patients not defined\", \"Residual protease function of the truncation not assessed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"CRISPR loss-of-function in C2C12 cells and zebrafish, plus mouse data, showed KY deficiency upregulates BAG3 and CASA factors and impairs their stress-induced adaptation, linking KY to chaperone-assisted selective autophagy-mediated FLNC turnover.\",\n      \"evidence\": \"CRISPR/Cas9 knockout in cells and zebrafish, swimming-challenge assay, and protein analysis in ky/ky mice\",\n      \"pmids\": [\"29914939\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between KY protease activity and CASA induction unresolved\", \"Whether CASA upregulation compensates for or contributes to pathology unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How KY protease activity is regulated and how its cleavage of filamin C is mechanistically coupled to titin signalling, NMJ stability, and CASA induction remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the KY catalytic domain or cleavage mechanism\", \"Catalytic residues and physiological substrate repertoire incompletely defined\", \"Direct mechanistic chain from KY loss to titin/CASA/NMJ phenotypes not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [\"KY–IGFN1–FLNC Z-band complex\"],\n    \"partners\": [\"FLNC\", \"IGFN1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}