{"gene":"KIF21A","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":1999,"finding":"KIF21A is a plus-end-directed kinesin motor protein enriched in neurons; KIF21A protein localizes throughout neurons (cell bodies, axons, and dendrites), whereas the closely related KIF21B is highly enriched in dendrites. KIF21A contains a domain of seven WD-40 repeats proposed to be involved in cargo binding.","method":"Subcellular localization by immunofluorescence/neuronal fractionation; motor domain characterization","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization experiments in neurons, single lab, but no functional rescue or mechanistic follow-up for the localization distinction","pmids":["10225949"],"is_preprint":false},{"year":2003,"finding":"Heterozygous missense mutations in KIF21A cause CFEOM1; six different mutations were identified in 44/45 probands, with primary mutational hotspots in the third coiled-coil stalk domain, establishing that the stalk domain plays a critical role in oculomotor axis formation.","method":"Direct DNA sequencing and mutation mapping across patient cohort","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — large patient cohort, multiple independent mutations clustered in the same domain, replicated across many subsequent studies","pmids":["14595441"],"is_preprint":false},{"year":2008,"finding":"KIF21A interacts with BIG1 (brefeldin A-inhibited guanine nucleotide-exchange protein 1); the C-terminal tail of KIF21A (containing seven WD-40 repeats) interacts with the C-terminal region of BIG1. Depletion of KIF21A by siRNA altered BIG1 distribution without changing intrinsic Golgi membrane proteins, implicating KIF21A in BIG1-dependent membrane trafficking.","method":"Co-immunoprecipitation (reciprocal IP of endogenous proteins), LC-MS/MS, overexpression of fragments, siRNA knockdown with subcellular distribution readout","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP of endogenous proteins plus siRNA phenotype, single lab, multiple orthogonal methods","pmids":["19020088"],"is_preprint":false},{"year":2009,"finding":"KIF21A interacts with KANK1 through its third and fourth coiled-coil stalk domains; the CFEOM1-associated mutations R954W and M947T enhance KIF21A heterodimer formation with wild-type KIF21A and also enhance binding to KANK1, leading to significantly increased translocation of KANK1 to the membrane fraction.","method":"Co-immunoprecipitation, subcellular fractionation, knockdown of KIF21A, overexpression of wild-type and mutant KIF21A constructs","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and fractionation with multiple constructs, single lab, consistent with later structural studies","pmids":["19559006"],"is_preprint":false},{"year":2012,"finding":"KIF21A is the anterograde motor responsible for polarized axonal transport of NCKX2 in hippocampal neurons; the intracellular loop of NCKX2 specifically interacts with the WD-40 repeat domain of KIF21A. Dominant-negative KIF21A or KIF21A knockdown inhibits NCKX2-GFP axonal transport and causes calcium dysregulation at axonal boutons.","method":"Co-immunoprecipitation (WD-40 domain interaction mapping), dominant-negative overexpression, siRNA knockdown, live-cell calcium imaging, live-cell immunocytochemistry of surface NCKX2","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP with domain mapping, dominant-negative, KD, functional calcium readout), single lab but rigorous","pmids":["22442075"],"is_preprint":false},{"year":2013,"finding":"KIF21A functions as an inhibitor of microtubule growth at the cell cortex: in vitro it suppresses microtubule growth and inhibits catastrophes; in cells it restricts microtubule growth at the cell edge. KIF21A is recruited to the cortex by KANK1, which co-clusters with liprin-α1/β1 and LL5β-containing cortical microtubule attachment complexes. CFEOM1 mutations relieve autoinhibition of the KIF21A motor, leading to enhanced KIF21A accumulation in axonal growth cones, aberrant axon morphology, and reduced responsiveness to inhibitory cues.","method":"In vitro microtubule dynamics assay (TIRF microscopy), live-cell imaging, co-immunoprecipitation, siRNA knockdown, overexpression of CFEOM1 mutants in neurons","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of microtubule suppression, cell-based assays, Co-IP, and CFEOM1 mutant functional analysis, single lab with multiple orthogonal methods","pmids":["24120883"],"is_preprint":false},{"year":2014,"finding":"CFEOM1-associated mutations in the motor domain and third coiled-coil stalk of KIF21A attenuate KIF21A autoinhibition (gain-of-function mechanism); knockin mice with the most common human mutation develop CFEOM with oculomotor axon stalling, enlarged growth cones, excessive filopodia, and ectopic branching. MAP1B was identified as a KIF21A-interacting protein, and Map1b-null mice also develop CFEOM.","method":"Knockin mouse model, axon morphology/tracing analysis, yeast two-hybrid and co-immunoprecipitation for MAP1B interaction, genetic epistasis (Map1b-/- phenotype)","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockin model with defined axon phenotype, Co-IP for MAP1B, genetic epistasis with Map1b KO, single lab but multiple orthogonal approaches","pmids":["24656932"],"is_preprint":false},{"year":2016,"finding":"The KIF21A stalk regulatory domain containing all CFEOM1-associated substitutions forms an intramolecular antiparallel coiled coil that mediates autoinhibition by binding the motor domain. CFEOM1 mutations hyperactivate KIF21A either by disrupting structural integrity of the antiparallel coiled coil or by reducing its affinity for the motor domain. This regulatory mechanism is conserved in KIF21B, KIF7, and KIF27.","method":"X-ray crystallography of regulatory domain, in vitro binding assays, mutagenesis of disease-associated residues, motor domain interaction assays","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure of regulatory domain plus mutagenesis plus in vitro binding assays, mechanistically rigorous single study","pmids":["27485312"],"is_preprint":false},{"year":2017,"finding":"Crystal structure of the KANK1 ankyrin repeat domain (ANKRD) in complex with a KIF21A peptide at high resolution reveals that target recognition involves combinatorial use of two interfaces on the ANKRD. Mutations in either interface disrupt the KANK1-KIF21A interaction and block recruitment of KIF21A to focal adhesions.","method":"X-ray crystallography, mutagenesis of binding interface residues, co-immunoprecipitation, cellular immunofluorescence localization","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with mutagenesis and cellular validation, single rigorous study with multiple orthogonal methods","pmids":["29217769"],"is_preprint":false},{"year":2017,"finding":"Crystal structure of the KANK1·KIF21A complex at 2.1 Å resolution shows that a five-helix-bundle-capping domain immediately preceding the ANK repeats of KANK1 forms a structural and functional supramodule with the ANK repeats to bind an evolutionarily conserved peptide in the middle of KIF21A. Cancer-associated missense mutations in KANK1 located at this interface destabilize the complex.","method":"X-ray crystallography (2.1 Å), biochemical binding assays, mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structure plus biochemical validation, single rigorous study","pmids":["29158259"],"is_preprint":false},{"year":2017,"finding":"A stretch of ~22 amino acids in KIF21A is sufficient for binding to both KANK1 and KANK2 ankyrin domains; in each complex structure, KIF21A adopts helical conformations upon binding and is recognized by two distinct pockets of the ankyrin domain.","method":"X-ray crystallography of KIF21A peptide with KANK1 and KANK2 ankyrin domains, site-directed mutagenesis, biochemical binding assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — two independent crystal structures plus mutagenesis and biochemical validation in one study","pmids":["29183992"],"is_preprint":false},{"year":2021,"finding":"An NS-associated KANK2 mutation (S684F) induces pathological binding of eIF4A1 at the physiological KIF21A-binding site of KANK2, competitively displacing KIF21A. In mouse podocytes, the S684F KANK2 mutant interfered with the KANK2/KIF21A interaction via eIF4A1 binding and failed to rescue focal adhesion or cell adhesion defects caused by KANK2 knockout.","method":"Structural analysis, biochemical co-immunoprecipitation, competitive binding assays, KANK2 knockout podocyte rescue experiments","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — structural and biochemical data plus cellular rescue assay, single lab, focused on KANK2 mutant but directly demonstrates KIF21A displacement","pmids":["34274317"],"is_preprint":false},{"year":2023,"finding":"KIF21A localizes to a subset of dendritic spines; KIF21A-positive spines are larger and more structurally plastic. The KIF21A–KANK1 interaction is required for dendritic spine morphogenesis, dendritic branching, and synaptic plasticity; knockdown of either KIF21A or KANK1 inhibits spine morphogenesis, and rescue requires the ability to bind both KANK1 (via KIF21A) and talin1 (via KANK1). KIF21A knockdown in rat hippocampus impairs LTP amplitude and cognitive performance.","method":"shRNA knockdown, rescue with binding-deficient mutants, immunofluorescence localization, LTP electrophysiology, behavioral (cognitive) testing","journal":"Neural regeneration research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown with binding-mutant rescue and in vivo LTP/behavioral readouts, single lab, multiple orthogonal methods","pmids":["38767486"],"is_preprint":false},{"year":2023,"finding":"Kif21a localizes specifically to podocytes in the zebrafish glomerulus; Kif21a deficiency causes podocyte foot process effacement, altered slit diaphragm formation, and severe proteinuria (leaky glomerular filtration barrier), establishing a role for KIF21A in podocyte architecture and glomerular filtration.","method":"Zebrafish loss-of-function model, immunofluorescence localization, electron microscopy of podocyte ultrastructure, functional proteinuria assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo loss-of-function with defined structural and functional readouts, single lab, zebrafish model","pmids":["37932480"],"is_preprint":false},{"year":2025,"finding":"A novel KIF21A variant (p.Leu664Pro) in the second coiled-coil domain, distinct from the autoinhibitory third coiled-coil domain, shows decreased binding to TUBB3 by co-immunoprecipitation in vitro, causing peripheral neuropathy rather than CFEOM, indicating that disruption of the KIF21A–TUBB3 interaction defines a mechanistically distinct disease phenotype.","method":"Co-immunoprecipitation (KIF21A variant vs. TUBB3), protein structure modelling, clinical/genetic characterization","journal":"Journal of medical genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP experiment for binding, protein modelling only for structure, single case report with limited mechanistic follow-up","pmids":["39643435"],"is_preprint":false}],"current_model":"KIF21A is an anterograde kinesin-4 motor that transports cargo (e.g., NCKX2) along axonal microtubules via its WD-40 repeat cargo-binding domain, and simultaneously inhibits microtubule growth at the cell cortex through an autoinhibitory mechanism in which the third coiled-coil stalk forms an antiparallel coiled coil that suppresses motor activity; CFEOM1-associated mutations in the motor domain or stalk relieve this autoinhibition, causing oculomotor axon stalling in vivo, while cortical recruitment of KIF21A depends on direct interaction with the KANK1/KANK2 ankyrin repeat domain (structurally resolved at high resolution), and KIF21A also interacts with MAP1B and BIG1 to regulate axon cytoskeleton and membrane trafficking, respectively."},"narrative":{"mechanistic_narrative":"KIF21A is a plus-end-directed, neuron-enriched kinesin-4 motor that couples anterograde axonal cargo transport with spatial control of microtubule growth at the cell cortex [PMID:10225949, PMID:24120883]. Through its C-terminal WD-40 repeat domain it binds cargo, including the K+-dependent Na+/Ca2+ exchanger NCKX2, whose polarized axonal delivery and consequent calcium homeostasis at boutons depend on KIF21A motor activity [PMID:22442075]. At the cell edge KIF21A acts as a microtubule growth inhibitor that suppresses polymerization and catastrophes, and is recruited to cortical microtubule attachment complexes by direct binding to the ankyrin-repeat domain of KANK1/KANK2 — an interaction resolved at high resolution showing a conserved ~22-residue KIF21A peptide engaging two pockets of the KANK ankyrin domain together with its capping supramodule [PMID:24120883, PMID:29217769, PMID:29158259, PMID:29183992]. Motor activity is held in check by an intramolecular autoinhibitory mechanism in which the third coiled-coil stalk forms an antiparallel coiled coil that binds and represses the motor domain [PMID:27485312]. Heterozygous missense mutations clustered in the motor domain and third stalk cause congenital fibrosis of the extraocular muscles type 1 (CFEOM1) by relieving this autoinhibition; a knockin mouse model reproduces the disease with oculomotor axon stalling, enlarged growth cones, and ectopic branching [PMID:14595441, PMID:24656932, PMID:27485312]. KIF21A additionally interacts with MAP1B to regulate axonal cytoskeleton and with BIG1 to control membrane trafficking [PMID:19020088, PMID:24656932], and the KIF21A–KANK1 axis supports dendritic spine morphogenesis, synaptic plasticity, and glomerular podocyte architecture [PMID:38767486, PMID:37932480].","teleology":[{"year":1999,"claim":"Established KIF21A as a plus-end-directed kinesin motor with a candidate cargo-binding module, distinguishing it from its dendrite-restricted paralog KIF21B.","evidence":"Subcellular localization by immunofluorescence and neuronal fractionation, motor domain characterization","pmids":["10225949"],"confidence":"Medium","gaps":["No cargo identified at this stage","WD-40 cargo-binding role only proposed, not functionally tested"]},{"year":2003,"claim":"Linked KIF21A to human disease by showing heterozygous missense mutations clustered in the third coiled-coil stalk cause CFEOM1, implicating the stalk in oculomotor axon development.","evidence":"Direct DNA sequencing and mutation mapping across a 45-proband cohort","pmids":["14595441"],"confidence":"High","gaps":["Molecular consequence of the mutations unknown","Did not establish gain- vs loss-of-function"]},{"year":2008,"claim":"Connected KIF21A to membrane trafficking by identifying BIG1 as a WD-40-domain partner whose distribution depends on KIF21A.","evidence":"Reciprocal endogenous Co-IP, LC-MS/MS, fragment overexpression, and siRNA with distribution readout","pmids":["19020088"],"confidence":"Medium","gaps":["No direct transport assay of BIG1 by KIF21A","Single lab, mechanism of trafficking control unresolved"]},{"year":2009,"claim":"Identified KANK1 as a stalk-domain partner and showed CFEOM1 mutations enhance both KIF21A self-association and KANK1 membrane translocation, hinting at altered protein interactions in disease.","evidence":"Co-IP, subcellular fractionation, knockdown, and wild-type/mutant construct overexpression","pmids":["19559006"],"confidence":"Medium","gaps":["Functional consequence of enhanced KANK1 translocation unclear","Did not yet define the autoinhibition framework"]},{"year":2012,"claim":"Defined a concrete cargo for KIF21A, showing it drives anterograde axonal transport of NCKX2 to control bouton calcium homeostasis.","evidence":"Co-IP with WD-40 domain mapping, dominant-negative, siRNA, and live-cell calcium/surface imaging in hippocampal neurons","pmids":["22442075"],"confidence":"High","gaps":["Whether other cargoes use the same WD-40 interface unknown","Link between cargo transport and CFEOM not established"]},{"year":2013,"claim":"Reframed KIF21A as a cortical microtubule growth inhibitor recruited by KANK1, and showed CFEOM1 mutations are activating by relieving autoinhibition.","evidence":"In vitro TIRF microtubule dynamics reconstitution, live-cell imaging, Co-IP, knockdown, and CFEOM1 mutant expression in neurons","pmids":["24120883"],"confidence":"High","gaps":["Structural basis of autoinhibition not yet defined","Mechanism of microtubule catastrophe suppression unresolved"]},{"year":2014,"claim":"Confirmed in vivo that CFEOM1 mutations are gain-of-function attenuating autoinhibition, producing oculomotor axon stalling, and identified MAP1B as a functionally relevant partner.","evidence":"Knockin mouse with axon tracing, yeast two-hybrid and Co-IP for MAP1B, and Map1b-null genetic epistasis","pmids":["24656932"],"confidence":"High","gaps":["Molecular interface of MAP1B binding not mapped","How motor hyperactivity translates to axon stalling not fully resolved"]},{"year":2016,"claim":"Provided the structural mechanism of autoinhibition, showing the stalk regulatory domain forms an antiparallel coiled coil that binds and represses the motor, with CFEOM1 mutations disrupting this fold.","evidence":"X-ray crystallography of the regulatory domain, in vitro binding, and disease-residue mutagenesis","pmids":["27485312"],"confidence":"High","gaps":["Dynamics of inhibition release in cells not directly visualized","Regulatory triggers for activation unknown"]},{"year":2017,"claim":"Resolved the structural basis of cortical recruitment, showing a conserved KIF21A peptide is bound by a KANK ankyrin-repeat supramodule via combinatorial interfaces shared by KANK1 and KANK2.","evidence":"Multiple high-resolution crystal structures of KANK1/KANK2 ANKRD–KIF21A peptide complexes, mutagenesis, biochemical binding, and focal-adhesion localization","pmids":["29217769","29158259","29183992"],"confidence":"High","gaps":["How recruitment couples to motor activation not defined","Regulation of the interaction in neurons not addressed"]},{"year":2021,"claim":"Showed the KANK2–KIF21A interface is disease-relevant, as a nephrotic-syndrome KANK2 mutation competitively displaces KIF21A via aberrant eIF4A1 binding and fails to rescue adhesion defects.","evidence":"Structural and biochemical competitive binding analysis with KANK2-knockout podocyte rescue","pmids":["34274317"],"confidence":"Medium","gaps":["KIF21A-side consequences of displacement not directly tested","Single lab, focused on the KANK2 mutant"]},{"year":2023,"claim":"Extended KIF21A function to dendritic spine plasticity and podocyte architecture, in both cases requiring the KANK-dependent adhesion linkage.","evidence":"shRNA knockdown with binding-mutant rescue, LTP electrophysiology and behavior in rat, and zebrafish loss-of-function with podocyte ultrastructure and proteinuria readouts","pmids":["38767486","37932480"],"confidence":"Medium","gaps":["Whether spine and podocyte roles use the same cortical microtubule mechanism unknown","Molecular cargo at spines/foot processes not identified"]},{"year":2025,"claim":"Suggested a mechanistically distinct disease axis, with a second coiled-coil variant reducing TUBB3 binding and causing peripheral neuropathy rather than CFEOM.","evidence":"Single Co-IP for TUBB3 binding, protein modelling, and clinical/genetic characterization of one case","pmids":["39643435"],"confidence":"Low","gaps":["Single Co-IP without reciprocal or functional validation","TUBB3-binding role of the second coiled coil not independently confirmed","Genotype-phenotype link rests on a single case"]},{"year":null,"claim":"How cortical recruitment, autoinhibition release, and cargo selection are temporally coordinated to direct distinct axonal, dendritic, and non-neuronal outcomes remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking motor activation to specific cargo at specific sites","Upstream signals controlling autoinhibition release unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003774","term_label":"cytoskeletal motor activity","supporting_discovery_ids":[0,4]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[5]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[5,6]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,7]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[5]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5,8]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[6,5]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[4,12]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[2,4]}],"complexes":["KANK1-KIF21A cortical microtubule attachment complex"],"partners":["KANK1","KANK2","NCKX2","BIG1","MAP1B","TUBB3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q7Z4S6","full_name":"Kinesin-like protein KIF21A","aliases":["Kinesin-like protein KIF2","Renal carcinoma antigen NY-REN-62"],"length_aa":1674,"mass_kda":187.2,"function":"Processive microtubule plus-end directed motor protein involved in neuronal axon guidance. Is recruited by KANK1 to cortical microtubule stabilizing complexes (CMSCs) at focal adhesions (FAs) rims where it promotes microtubule capture and stability. Controls microtubule polymerization rate at axonal growth cones and suppresses microtubule growth without inducing microtubule disassembly once it reaches the cell cortex","subcellular_location":"Cytoplasm, cytoskeleton; Cytoplasm, cell cortex; Cell projection, axon; Cell projection, dendrite; Cell projection, growth cone","url":"https://www.uniprot.org/uniprotkb/Q7Z4S6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KIF21A","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/KIF21A","total_profiled":1310},"omim":[{"mim_id":"608322","title":"KINESIN FAMILY MEMBER 21B; KIF21B","url":"https://www.omim.org/entry/608322"},{"mim_id":"608283","title":"KINESIN FAMILY MEMBER 21A; KIF21A","url":"https://www.omim.org/entry/608283"},{"mim_id":"602661","title":"TUBULIN, BETA-3; TUBB3","url":"https://www.omim.org/entry/602661"},{"mim_id":"600638","title":"FIBROSIS OF EXTRAOCULAR MUSCLES, CONGENITAL, 3A, WITH OR WITHOUT EXTRAOCULAR INVOLVEMENT; CFEOM3A","url":"https://www.omim.org/entry/600638"},{"mim_id":"167410","title":"PAIRED BOX GENE 7; PAX7","url":"https://www.omim.org/entry/167410"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"retina","ntpm":71.9}],"url":"https://www.proteinatlas.org/search/KIF21A"},"hgnc":{"alias_symbol":["FLJ20052"],"prev_symbol":["FEOM1"]},"alphafold":{"accession":"Q7Z4S6","domains":[{"cath_id":"3.40.850.10","chopping":"12-164_174-242_262-379","consensus_level":"medium","plddt":88.9711,"start":12,"end":379},{"cath_id":"-","chopping":"940-1083","consensus_level":"medium","plddt":81.6947,"start":940,"end":1083},{"cath_id":"2.130.10.10","chopping":"1323-1438_1450-1654","consensus_level":"medium","plddt":90.6566,"start":1323,"end":1654},{"cath_id":"1.10.287","chopping":"643-704_712-827","consensus_level":"medium","plddt":80.8466,"start":643,"end":827}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7Z4S6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q7Z4S6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q7Z4S6-F1-predicted_aligned_error_v6.png","plddt_mean":70.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KIF21A","jax_strain_url":"https://www.jax.org/strain/search?query=KIF21A"},"sequence":{"accession":"Q7Z4S6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q7Z4S6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q7Z4S6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7Z4S6"}},"corpus_meta":[{"pmid":"14595441","id":"PMC_14595441","title":"Heterozygous mutations of the kinesin KIF21A in congenital fibrosis of the extraocular muscles type 1 (CFEOM1).","date":"2003","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/14595441","citation_count":201,"is_preprint":false},{"pmid":"24120883","id":"PMC_24120883","title":"CFEOM1-associated kinesin KIF21A is a cortical microtubule growth inhibitor.","date":"2013","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/24120883","citation_count":153,"is_preprint":false},{"pmid":"10225949","id":"PMC_10225949","title":"Novel dendritic kinesin sorting identified by different process targeting of two related kinesins: KIF21A and KIF21B.","date":"1999","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/10225949","citation_count":142,"is_preprint":false},{"pmid":"24656932","id":"PMC_24656932","title":"Human CFEOM1 mutations attenuate KIF21A autoinhibition and cause oculomotor axon stalling.","date":"2014","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/24656932","citation_count":94,"is_preprint":false},{"pmid":"15223798","id":"PMC_15223798","title":"Identification of KIF21A mutations as a rare cause of congenital fibrosis of the extraocular muscles type 3 (CFEOM3).","date":"2004","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/15223798","citation_count":74,"is_preprint":false},{"pmid":"16157808","id":"PMC_16157808","title":"A novel KIF21A mutation in a patient with congenital fibrosis of the extraocular muscles and Marcus Gunn jaw-winking phenomenon.","date":"2005","source":"Archives of ophthalmology (Chicago, Ill. : 1960)","url":"https://pubmed.ncbi.nlm.nih.gov/16157808","citation_count":41,"is_preprint":false},{"pmid":"17511870","id":"PMC_17511870","title":"Three novel mutations in KIF21A highlight the importance of the third coiled-coil stalk domain in the etiology of CFEOM1.","date":"2007","source":"BMC genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17511870","citation_count":41,"is_preprint":false},{"pmid":"34740919","id":"PMC_34740919","title":"Bi-allelic loss-of-function variants in KIF21A cause severe fetal akinesia with arthrogryposis multiplex.","date":"2021","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34740919","citation_count":37,"is_preprint":false},{"pmid":"22442075","id":"PMC_22442075","title":"KIF21A-mediated axonal transport and selective endocytosis underlie the polarized targeting of NCKX2.","date":"2012","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/22442075","citation_count":30,"is_preprint":false},{"pmid":"19559006","id":"PMC_19559006","title":"A major mutation of KIF21A associated with congenital fibrosis of the extraocular muscles type 1 (CFEOM1) enhances translocation of Kank1 to the membrane.","date":"2009","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/19559006","citation_count":30,"is_preprint":false},{"pmid":"18332320","id":"PMC_18332320","title":"Novel and recurrent KIF21A mutations in congenital fibrosis of the extraocular muscles type 1 and 3.","date":"2008","source":"Archives of ophthalmology (Chicago, Ill. : 1960)","url":"https://pubmed.ncbi.nlm.nih.gov/18332320","citation_count":29,"is_preprint":false},{"pmid":"19020088","id":"PMC_19020088","title":"Interaction of brefeldin A-inhibited guanine nucleotide-exchange protein (BIG) 1 and kinesin motor protein KIF21A.","date":"2008","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/19020088","citation_count":28,"is_preprint":false},{"pmid":"29217769","id":"PMC_29217769","title":"Structural insights into ankyrin repeat-mediated recognition of the kinesin motor protein KIF21A by KANK1, a scaffold protein in focal adhesion.","date":"2017","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29217769","citation_count":25,"is_preprint":false},{"pmid":"37600020","id":"PMC_37600020","title":"TUBB3 and KIF21A in neurodevelopment and disease.","date":"2023","source":"Frontiers in neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/37600020","citation_count":23,"is_preprint":false},{"pmid":"27485312","id":"PMC_27485312","title":"Structural basis for misregulation of kinesin KIF21A autoinhibition by CFEOM1 disease mutations.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27485312","citation_count":23,"is_preprint":false},{"pmid":"15827546","id":"PMC_15827546","title":"KIF21A gene c.2860C>T mutation in congenital fibrosis of extraocular muscles type 1 and 3.","date":"2005","source":"Molecular vision","url":"https://pubmed.ncbi.nlm.nih.gov/15827546","citation_count":20,"is_preprint":false},{"pmid":"22465342","id":"PMC_22465342","title":"Spatiotemporal expression pattern of KIF21A during normal embryonic development and in congenital fibrosis of the extraocular muscles type 1 (CFEOM1).","date":"2012","source":"Gene expression patterns : GEP","url":"https://pubmed.ncbi.nlm.nih.gov/22465342","citation_count":19,"is_preprint":false},{"pmid":"15621876","id":"PMC_15621876","title":"Mutation analysis of KIF21A in congenital fibrosis of the extraocular muscles (CFEOM) patients.","date":"2004","source":"Ophthalmic genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15621876","citation_count":18,"is_preprint":false},{"pmid":"15621877","id":"PMC_15621877","title":"Mutation analysis of the KIF21A gene in an Indian family with CFEOM1: implication of CpG methylation for most frequent mutations.","date":"2004","source":"Ophthalmic genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15621877","citation_count":17,"is_preprint":false},{"pmid":"21805025","id":"PMC_21805025","title":"KIF21A novel deletion and recurrent mutation in patients with congenital fibrosis of the extraocular muscles-1.","date":"2011","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/21805025","citation_count":16,"is_preprint":false},{"pmid":"29158259","id":"PMC_29158259","title":"Structural analyses of key features in the KANK1·KIF21A complex yield mechanistic insights into the cross-talk between microtubules and the cell cortex.","date":"2017","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29158259","citation_count":15,"is_preprint":false},{"pmid":"29183992","id":"PMC_29183992","title":"Structural basis for the recognition of kinesin family member 21A (KIF21A) by the ankyrin domains of KANK1 and KANK2 proteins.","date":"2017","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29183992","citation_count":15,"is_preprint":false},{"pmid":"21042561","id":"PMC_21042561","title":"KIF21A mutations in two Chinese families with congenital fibrosis of the extraocular muscles (CFEOM).","date":"2010","source":"Molecular vision","url":"https://pubmed.ncbi.nlm.nih.gov/21042561","citation_count":14,"is_preprint":false},{"pmid":"12899874","id":"PMC_12899874","title":"A Japanese family with FEOM1-linked congenital fibrosis of the extraocular muscles type 1 associated with spinal canal stenosis and refinement of the FEOM1 critical region.","date":"2003","source":"Neuromuscular disorders : NMD","url":"https://pubmed.ncbi.nlm.nih.gov/12899874","citation_count":13,"is_preprint":false},{"pmid":"24715754","id":"PMC_24715754","title":"A novel de novo KIF21A mutation in a patient with congenital fibrosis of the extraocular muscles and Möbius syndrome.","date":"2014","source":"Molecular vision","url":"https://pubmed.ncbi.nlm.nih.gov/24715754","citation_count":13,"is_preprint":false},{"pmid":"19896199","id":"PMC_19896199","title":"Germline Mosaicism for KIF21A Mutation (p.R954L) Mimicking Recessive Inheritance for Congenital Fibrosis of the Extraocular Muscles.","date":"2009","source":"Ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/19896199","citation_count":13,"is_preprint":false},{"pmid":"16365788","id":"PMC_16365788","title":"Recurrent mutation of the KIF21A gene in Japanese patients with congenital fibrosis of the extraocular muscles.","date":"2005","source":"Japanese journal of ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/16365788","citation_count":10,"is_preprint":false},{"pmid":"21264235","id":"PMC_21264235","title":"Lack of KIF21A mutations in congenital fibrosis of the extraocular muscles type I patients from consanguineous Saudi Arabian families.","date":"2011","source":"Molecular vision","url":"https://pubmed.ncbi.nlm.nih.gov/21264235","citation_count":10,"is_preprint":false},{"pmid":"38767486","id":"PMC_38767486","title":"The interaction between KIF21A and KANK1 regulates dendritic morphology and synapse plasticity in neurons.","date":"2023","source":"Neural regeneration research","url":"https://pubmed.ncbi.nlm.nih.gov/38767486","citation_count":9,"is_preprint":false},{"pmid":"26190014","id":"PMC_26190014","title":"A rare case of congenital fibrosis of extraocular muscle type 1A due to KIF21A mutation with Marcus Gunn jaw-winking phenomenon.","date":"2015","source":"European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society","url":"https://pubmed.ncbi.nlm.nih.gov/26190014","citation_count":9,"is_preprint":false},{"pmid":"33251926","id":"PMC_33251926","title":"KIF21A pathogenic variants cause congenital fibrosis of extraocular muscles type 3.","date":"2020","source":"Ophthalmic genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33251926","citation_count":8,"is_preprint":false},{"pmid":"19551685","id":"PMC_19551685","title":"KIF21A variant R954W in familial or sporadic cases of CFEOM1.","date":"2009","source":"European journal of ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/19551685","citation_count":7,"is_preprint":false},{"pmid":"22968744","id":"PMC_22968744","title":"KIF21A mRNA expression in patients with Down syndrome.","date":"2012","source":"Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology","url":"https://pubmed.ncbi.nlm.nih.gov/22968744","citation_count":7,"is_preprint":false},{"pmid":"34274317","id":"PMC_34274317","title":"Nephrotic-syndrome-associated mutation of KANK2 induces pathologic binding competition with physiological interactor KIF21A.","date":"2021","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/34274317","citation_count":5,"is_preprint":false},{"pmid":"23799907","id":"PMC_23799907","title":"Inherited KIF21A and PAX6 gene mutations in a boy with congenital fibrosis of extraocular muscles and aniridia.","date":"2013","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23799907","citation_count":5,"is_preprint":false},{"pmid":"16939002","id":"PMC_16939002","title":"Mutation p.Arg954Trp of KIF21A causes congenital fibrosis of the extraocular muscles in a Chinese family.","date":"2006","source":"Yi chuan xue bao = Acta genetica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/16939002","citation_count":5,"is_preprint":false},{"pmid":"28930843","id":"PMC_28930843","title":"Clinical characteristics of a KIF21A mutation in a Chinese family with congenital fibrosis of the extraocular muscles type 1.","date":"2017","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28930843","citation_count":4,"is_preprint":false},{"pmid":"24426772","id":"PMC_24426772","title":"Maternal germline mosaicism of kinesin family member 21A (KIF21A) mutation causes complex phenotypes in a Chinese family with congenital fibrosis of the extraocular muscles.","date":"2014","source":"Molecular vision","url":"https://pubmed.ncbi.nlm.nih.gov/24426772","citation_count":4,"is_preprint":false},{"pmid":"37921537","id":"PMC_37921537","title":"Phenotypic heterogeneity associated with KIF21A: Two new cases and review of the literature.","date":"2023","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/37921537","citation_count":3,"is_preprint":false},{"pmid":"27513105","id":"PMC_27513105","title":"KIF21A mutation in two Chinese families with congenital fibrosis of the extraocular muscles type 1 and 3.","date":"2016","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/27513105","citation_count":3,"is_preprint":false},{"pmid":"23336411","id":"PMC_23336411","title":"[R954 mutations in KIF21A gene in Chinese patients with congenital fibrosis of extraocular muscles].","date":"2012","source":"[Zhonghua yan ke za zhi] Chinese journal of ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/23336411","citation_count":3,"is_preprint":false},{"pmid":"32686171","id":"PMC_32686171","title":"A 63-bp insertion in exon 2 of the porcine KIF21A gene is associated with arthrogryposis multiplex congenita.","date":"2020","source":"Animal genetics","url":"https://pubmed.ncbi.nlm.nih.gov/32686171","citation_count":3,"is_preprint":false},{"pmid":"35280030","id":"PMC_35280030","title":"[Identification of a novel KIF21A gene mutation in a Chinese family with congenital fibrosis of the extraocular muscles].","date":"2022","source":"[Zhonghua yan ke za zhi] Chinese journal of ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/35280030","citation_count":3,"is_preprint":false},{"pmid":"37932480","id":"PMC_37932480","title":"Kif21a deficiency leads to impaired glomerular filtration barrier function.","date":"2023","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/37932480","citation_count":2,"is_preprint":false},{"pmid":"30555664","id":"PMC_30555664","title":"KIF21A Gene c.2860C>T Mutation in CFEOM1A: The First Report from Iran.","date":"2018","source":"Avicenna journal of medical biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/30555664","citation_count":2,"is_preprint":false},{"pmid":"21983718","id":"PMC_21983718","title":"[Mutation analysis of KIF21A gene in a Chinese family with congenital fibrosis of the extraocular muscles type I].","date":"2011","source":"Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21983718","citation_count":2,"is_preprint":false},{"pmid":"23535681","id":"PMC_23535681","title":"Congenital fibrosis of extraocular muscle type 1A due to KIF21A mutation: first case report from Hong Kong.","date":"2013","source":"Hong Kong medical journal = Xianggang yi xue za zhi","url":"https://pubmed.ncbi.nlm.nih.gov/23535681","citation_count":2,"is_preprint":false},{"pmid":"39643435","id":"PMC_39643435","title":"KIF21A-associated peripheral neuropathy defined by impaired binding with TUBB3.","date":"2025","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39643435","citation_count":1,"is_preprint":false},{"pmid":"41282472","id":"PMC_41282472","title":"Case Report: autosomal dominant distal motor neuropathy as a new phenotype of KIF21A-related disorders.","date":"2025","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/41282472","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.05.27.656302","title":"Functionally distinct ALK and ROS1 fusions detected in infant-type hemispheric gliomas converge on STAT3 and SHP2 activation","date":"2025-05-31","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.27.656302","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":23937,"output_tokens":3955,"usd":0.065568,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11829,"output_tokens":3962,"usd":0.079098,"stage2_stop_reason":"end_turn"},"total_usd":0.144666,"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\": 1999,\n      \"finding\": \"KIF21A is a plus-end-directed kinesin motor protein enriched in neurons; KIF21A protein localizes throughout neurons (cell bodies, axons, and dendrites), whereas the closely related KIF21B is highly enriched in dendrites. KIF21A contains a domain of seven WD-40 repeats proposed to be involved in cargo binding.\",\n      \"method\": \"Subcellular localization by immunofluorescence/neuronal fractionation; motor domain characterization\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization experiments in neurons, single lab, but no functional rescue or mechanistic follow-up for the localization distinction\",\n      \"pmids\": [\"10225949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Heterozygous missense mutations in KIF21A cause CFEOM1; six different mutations were identified in 44/45 probands, with primary mutational hotspots in the third coiled-coil stalk domain, establishing that the stalk domain plays a critical role in oculomotor axis formation.\",\n      \"method\": \"Direct DNA sequencing and mutation mapping across patient cohort\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — large patient cohort, multiple independent mutations clustered in the same domain, replicated across many subsequent studies\",\n      \"pmids\": [\"14595441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"KIF21A interacts with BIG1 (brefeldin A-inhibited guanine nucleotide-exchange protein 1); the C-terminal tail of KIF21A (containing seven WD-40 repeats) interacts with the C-terminal region of BIG1. Depletion of KIF21A by siRNA altered BIG1 distribution without changing intrinsic Golgi membrane proteins, implicating KIF21A in BIG1-dependent membrane trafficking.\",\n      \"method\": \"Co-immunoprecipitation (reciprocal IP of endogenous proteins), LC-MS/MS, overexpression of fragments, siRNA knockdown with subcellular distribution readout\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP of endogenous proteins plus siRNA phenotype, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"19020088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"KIF21A interacts with KANK1 through its third and fourth coiled-coil stalk domains; the CFEOM1-associated mutations R954W and M947T enhance KIF21A heterodimer formation with wild-type KIF21A and also enhance binding to KANK1, leading to significantly increased translocation of KANK1 to the membrane fraction.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, knockdown of KIF21A, overexpression of wild-type and mutant KIF21A constructs\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and fractionation with multiple constructs, single lab, consistent with later structural studies\",\n      \"pmids\": [\"19559006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"KIF21A is the anterograde motor responsible for polarized axonal transport of NCKX2 in hippocampal neurons; the intracellular loop of NCKX2 specifically interacts with the WD-40 repeat domain of KIF21A. Dominant-negative KIF21A or KIF21A knockdown inhibits NCKX2-GFP axonal transport and causes calcium dysregulation at axonal boutons.\",\n      \"method\": \"Co-immunoprecipitation (WD-40 domain interaction mapping), dominant-negative overexpression, siRNA knockdown, live-cell calcium imaging, live-cell immunocytochemistry of surface NCKX2\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP with domain mapping, dominant-negative, KD, functional calcium readout), single lab but rigorous\",\n      \"pmids\": [\"22442075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"KIF21A functions as an inhibitor of microtubule growth at the cell cortex: in vitro it suppresses microtubule growth and inhibits catastrophes; in cells it restricts microtubule growth at the cell edge. KIF21A is recruited to the cortex by KANK1, which co-clusters with liprin-α1/β1 and LL5β-containing cortical microtubule attachment complexes. CFEOM1 mutations relieve autoinhibition of the KIF21A motor, leading to enhanced KIF21A accumulation in axonal growth cones, aberrant axon morphology, and reduced responsiveness to inhibitory cues.\",\n      \"method\": \"In vitro microtubule dynamics assay (TIRF microscopy), live-cell imaging, co-immunoprecipitation, siRNA knockdown, overexpression of CFEOM1 mutants in neurons\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of microtubule suppression, cell-based assays, Co-IP, and CFEOM1 mutant functional analysis, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"24120883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CFEOM1-associated mutations in the motor domain and third coiled-coil stalk of KIF21A attenuate KIF21A autoinhibition (gain-of-function mechanism); knockin mice with the most common human mutation develop CFEOM with oculomotor axon stalling, enlarged growth cones, excessive filopodia, and ectopic branching. MAP1B was identified as a KIF21A-interacting protein, and Map1b-null mice also develop CFEOM.\",\n      \"method\": \"Knockin mouse model, axon morphology/tracing analysis, yeast two-hybrid and co-immunoprecipitation for MAP1B interaction, genetic epistasis (Map1b-/- phenotype)\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockin model with defined axon phenotype, Co-IP for MAP1B, genetic epistasis with Map1b KO, single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"24656932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The KIF21A stalk regulatory domain containing all CFEOM1-associated substitutions forms an intramolecular antiparallel coiled coil that mediates autoinhibition by binding the motor domain. CFEOM1 mutations hyperactivate KIF21A either by disrupting structural integrity of the antiparallel coiled coil or by reducing its affinity for the motor domain. This regulatory mechanism is conserved in KIF21B, KIF7, and KIF27.\",\n      \"method\": \"X-ray crystallography of regulatory domain, in vitro binding assays, mutagenesis of disease-associated residues, motor domain interaction assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure of regulatory domain plus mutagenesis plus in vitro binding assays, mechanistically rigorous single study\",\n      \"pmids\": [\"27485312\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Crystal structure of the KANK1 ankyrin repeat domain (ANKRD) in complex with a KIF21A peptide at high resolution reveals that target recognition involves combinatorial use of two interfaces on the ANKRD. Mutations in either interface disrupt the KANK1-KIF21A interaction and block recruitment of KIF21A to focal adhesions.\",\n      \"method\": \"X-ray crystallography, mutagenesis of binding interface residues, co-immunoprecipitation, cellular immunofluorescence localization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with mutagenesis and cellular validation, single rigorous study with multiple orthogonal methods\",\n      \"pmids\": [\"29217769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Crystal structure of the KANK1·KIF21A complex at 2.1 Å resolution shows that a five-helix-bundle-capping domain immediately preceding the ANK repeats of KANK1 forms a structural and functional supramodule with the ANK repeats to bind an evolutionarily conserved peptide in the middle of KIF21A. Cancer-associated missense mutations in KANK1 located at this interface destabilize the complex.\",\n      \"method\": \"X-ray crystallography (2.1 Å), biochemical binding assays, mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structure plus biochemical validation, single rigorous study\",\n      \"pmids\": [\"29158259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A stretch of ~22 amino acids in KIF21A is sufficient for binding to both KANK1 and KANK2 ankyrin domains; in each complex structure, KIF21A adopts helical conformations upon binding and is recognized by two distinct pockets of the ankyrin domain.\",\n      \"method\": \"X-ray crystallography of KIF21A peptide with KANK1 and KANK2 ankyrin domains, site-directed mutagenesis, biochemical binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — two independent crystal structures plus mutagenesis and biochemical validation in one study\",\n      \"pmids\": [\"29183992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"An NS-associated KANK2 mutation (S684F) induces pathological binding of eIF4A1 at the physiological KIF21A-binding site of KANK2, competitively displacing KIF21A. In mouse podocytes, the S684F KANK2 mutant interfered with the KANK2/KIF21A interaction via eIF4A1 binding and failed to rescue focal adhesion or cell adhesion defects caused by KANK2 knockout.\",\n      \"method\": \"Structural analysis, biochemical co-immunoprecipitation, competitive binding assays, KANK2 knockout podocyte rescue experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — structural and biochemical data plus cellular rescue assay, single lab, focused on KANK2 mutant but directly demonstrates KIF21A displacement\",\n      \"pmids\": [\"34274317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KIF21A localizes to a subset of dendritic spines; KIF21A-positive spines are larger and more structurally plastic. The KIF21A–KANK1 interaction is required for dendritic spine morphogenesis, dendritic branching, and synaptic plasticity; knockdown of either KIF21A or KANK1 inhibits spine morphogenesis, and rescue requires the ability to bind both KANK1 (via KIF21A) and talin1 (via KANK1). KIF21A knockdown in rat hippocampus impairs LTP amplitude and cognitive performance.\",\n      \"method\": \"shRNA knockdown, rescue with binding-deficient mutants, immunofluorescence localization, LTP electrophysiology, behavioral (cognitive) testing\",\n      \"journal\": \"Neural regeneration research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown with binding-mutant rescue and in vivo LTP/behavioral readouts, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"38767486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Kif21a localizes specifically to podocytes in the zebrafish glomerulus; Kif21a deficiency causes podocyte foot process effacement, altered slit diaphragm formation, and severe proteinuria (leaky glomerular filtration barrier), establishing a role for KIF21A in podocyte architecture and glomerular filtration.\",\n      \"method\": \"Zebrafish loss-of-function model, immunofluorescence localization, electron microscopy of podocyte ultrastructure, functional proteinuria assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo loss-of-function with defined structural and functional readouts, single lab, zebrafish model\",\n      \"pmids\": [\"37932480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A novel KIF21A variant (p.Leu664Pro) in the second coiled-coil domain, distinct from the autoinhibitory third coiled-coil domain, shows decreased binding to TUBB3 by co-immunoprecipitation in vitro, causing peripheral neuropathy rather than CFEOM, indicating that disruption of the KIF21A–TUBB3 interaction defines a mechanistically distinct disease phenotype.\",\n      \"method\": \"Co-immunoprecipitation (KIF21A variant vs. TUBB3), protein structure modelling, clinical/genetic characterization\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP experiment for binding, protein modelling only for structure, single case report with limited mechanistic follow-up\",\n      \"pmids\": [\"39643435\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KIF21A is an anterograde kinesin-4 motor that transports cargo (e.g., NCKX2) along axonal microtubules via its WD-40 repeat cargo-binding domain, and simultaneously inhibits microtubule growth at the cell cortex through an autoinhibitory mechanism in which the third coiled-coil stalk forms an antiparallel coiled coil that suppresses motor activity; CFEOM1-associated mutations in the motor domain or stalk relieve this autoinhibition, causing oculomotor axon stalling in vivo, while cortical recruitment of KIF21A depends on direct interaction with the KANK1/KANK2 ankyrin repeat domain (structurally resolved at high resolution), and KIF21A also interacts with MAP1B and BIG1 to regulate axon cytoskeleton and membrane trafficking, respectively.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KIF21A is a plus-end-directed, neuron-enriched kinesin-4 motor that couples anterograde axonal cargo transport with spatial control of microtubule growth at the cell cortex [#0, #5]. Through its C-terminal WD-40 repeat domain it binds cargo, including the K+-dependent Na+/Ca2+ exchanger NCKX2, whose polarized axonal delivery and consequent calcium homeostasis at boutons depend on KIF21A motor activity [#4]. At the cell edge KIF21A acts as a microtubule growth inhibitor that suppresses polymerization and catastrophes, and is recruited to cortical microtubule attachment complexes by direct binding to the ankyrin-repeat domain of KANK1/KANK2 — an interaction resolved at high resolution showing a conserved ~22-residue KIF21A peptide engaging two pockets of the KANK ankyrin domain together with its capping supramodule [#5, #8, #9, #10]. Motor activity is held in check by an intramolecular autoinhibitory mechanism in which the third coiled-coil stalk forms an antiparallel coiled coil that binds and represses the motor domain [#7]. Heterozygous missense mutations clustered in the motor domain and third stalk cause congenital fibrosis of the extraocular muscles type 1 (CFEOM1) by relieving this autoinhibition; a knockin mouse model reproduces the disease with oculomotor axon stalling, enlarged growth cones, and ectopic branching [#1, #6, #7]. KIF21A additionally interacts with MAP1B to regulate axonal cytoskeleton and with BIG1 to control membrane trafficking [#2, #6], and the KIF21A–KANK1 axis supports dendritic spine morphogenesis, synaptic plasticity, and glomerular podocyte architecture [#12, #13].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established KIF21A as a plus-end-directed kinesin motor with a candidate cargo-binding module, distinguishing it from its dendrite-restricted paralog KIF21B.\",\n      \"evidence\": \"Subcellular localization by immunofluorescence and neuronal fractionation, motor domain characterization\",\n      \"pmids\": [\"10225949\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No cargo identified at this stage\", \"WD-40 cargo-binding role only proposed, not functionally tested\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Linked KIF21A to human disease by showing heterozygous missense mutations clustered in the third coiled-coil stalk cause CFEOM1, implicating the stalk in oculomotor axon development.\",\n      \"evidence\": \"Direct DNA sequencing and mutation mapping across a 45-proband cohort\",\n      \"pmids\": [\"14595441\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular consequence of the mutations unknown\", \"Did not establish gain- vs loss-of-function\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Connected KIF21A to membrane trafficking by identifying BIG1 as a WD-40-domain partner whose distribution depends on KIF21A.\",\n      \"evidence\": \"Reciprocal endogenous Co-IP, LC-MS/MS, fragment overexpression, and siRNA with distribution readout\",\n      \"pmids\": [\"19020088\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct transport assay of BIG1 by KIF21A\", \"Single lab, mechanism of trafficking control unresolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified KANK1 as a stalk-domain partner and showed CFEOM1 mutations enhance both KIF21A self-association and KANK1 membrane translocation, hinting at altered protein interactions in disease.\",\n      \"evidence\": \"Co-IP, subcellular fractionation, knockdown, and wild-type/mutant construct overexpression\",\n      \"pmids\": [\"19559006\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of enhanced KANK1 translocation unclear\", \"Did not yet define the autoinhibition framework\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined a concrete cargo for KIF21A, showing it drives anterograde axonal transport of NCKX2 to control bouton calcium homeostasis.\",\n      \"evidence\": \"Co-IP with WD-40 domain mapping, dominant-negative, siRNA, and live-cell calcium/surface imaging in hippocampal neurons\",\n      \"pmids\": [\"22442075\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other cargoes use the same WD-40 interface unknown\", \"Link between cargo transport and CFEOM not established\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Reframed KIF21A as a cortical microtubule growth inhibitor recruited by KANK1, and showed CFEOM1 mutations are activating by relieving autoinhibition.\",\n      \"evidence\": \"In vitro TIRF microtubule dynamics reconstitution, live-cell imaging, Co-IP, knockdown, and CFEOM1 mutant expression in neurons\",\n      \"pmids\": [\"24120883\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of autoinhibition not yet defined\", \"Mechanism of microtubule catastrophe suppression unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Confirmed in vivo that CFEOM1 mutations are gain-of-function attenuating autoinhibition, producing oculomotor axon stalling, and identified MAP1B as a functionally relevant partner.\",\n      \"evidence\": \"Knockin mouse with axon tracing, yeast two-hybrid and Co-IP for MAP1B, and Map1b-null genetic epistasis\",\n      \"pmids\": [\"24656932\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular interface of MAP1B binding not mapped\", \"How motor hyperactivity translates to axon stalling not fully resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Provided the structural mechanism of autoinhibition, showing the stalk regulatory domain forms an antiparallel coiled coil that binds and represses the motor, with CFEOM1 mutations disrupting this fold.\",\n      \"evidence\": \"X-ray crystallography of the regulatory domain, in vitro binding, and disease-residue mutagenesis\",\n      \"pmids\": [\"27485312\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dynamics of inhibition release in cells not directly visualized\", \"Regulatory triggers for activation unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Resolved the structural basis of cortical recruitment, showing a conserved KIF21A peptide is bound by a KANK ankyrin-repeat supramodule via combinatorial interfaces shared by KANK1 and KANK2.\",\n      \"evidence\": \"Multiple high-resolution crystal structures of KANK1/KANK2 ANKRD–KIF21A peptide complexes, mutagenesis, biochemical binding, and focal-adhesion localization\",\n      \"pmids\": [\"29217769\", \"29158259\", \"29183992\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How recruitment couples to motor activation not defined\", \"Regulation of the interaction in neurons not addressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed the KANK2–KIF21A interface is disease-relevant, as a nephrotic-syndrome KANK2 mutation competitively displaces KIF21A via aberrant eIF4A1 binding and fails to rescue adhesion defects.\",\n      \"evidence\": \"Structural and biochemical competitive binding analysis with KANK2-knockout podocyte rescue\",\n      \"pmids\": [\"34274317\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"KIF21A-side consequences of displacement not directly tested\", \"Single lab, focused on the KANK2 mutant\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended KIF21A function to dendritic spine plasticity and podocyte architecture, in both cases requiring the KANK-dependent adhesion linkage.\",\n      \"evidence\": \"shRNA knockdown with binding-mutant rescue, LTP electrophysiology and behavior in rat, and zebrafish loss-of-function with podocyte ultrastructure and proteinuria readouts\",\n      \"pmids\": [\"38767486\", \"37932480\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether spine and podocyte roles use the same cortical microtubule mechanism unknown\", \"Molecular cargo at spines/foot processes not identified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Suggested a mechanistically distinct disease axis, with a second coiled-coil variant reducing TUBB3 binding and causing peripheral neuropathy rather than CFEOM.\",\n      \"evidence\": \"Single Co-IP for TUBB3 binding, protein modelling, and clinical/genetic characterization of one case\",\n      \"pmids\": [\"39643435\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP without reciprocal or functional validation\", \"TUBB3-binding role of the second coiled coil not independently confirmed\", \"Genotype-phenotype link rests on a single case\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How cortical recruitment, autoinhibition release, and cargo selection are temporally coordinated to direct distinct axonal, dendritic, and non-neuronal outcomes remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking motor activation to specific cargo at specific sites\", \"Upstream signals controlling autoinhibition release unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003774\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5, 8]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [6, 5]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [4, 12]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [2, 4]}\n    ],\n    \"complexes\": [\"KANK1-KIF21A cortical microtubule attachment complex\"],\n    \"partners\": [\"KANK1\", \"KANK2\", \"NCKX2\", \"BIG1\", \"MAP1B\", \"TUBB3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}