{"gene":"KATNAL2","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2015,"finding":"KATNAL2 exists as a family of five alternatively spliced isoforms in mouse; these isoforms localize to interphase microtubules, centrioles, mitotic spindle, midbody, and the axoneme/basal body of sensory cilia. shRNAi knockdown causes inefficient cytokinesis, enlarged cells and nuclei, increased centriole numbers, aberrant multipolar mitotic spindles, chromosome bridges, multinuclearity, increased MT acetylation, and an altered cell cycle pattern. Silencing or stable overexpression of KATNAL2 isoforms drastically reduces ciliogenesis.","method":"shRNAi knockdown, stable overexpression, subcellular localization by immunofluorescence in cultured murine cells","journal":"Cellular and molecular life sciences : CMLS","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (KD, OE, localization), replicated across multiple isoforms with specific cellular phenotypic readouts in a single rigorous study","pmids":["26153462"],"is_preprint":false},{"year":2015,"finding":"KATNAL2 isoforms directly interact with nucleotide-binding proteins Nubp1 and Nubp2 (MRP/MinD-type P-loop NTPases that are integral centriole components and negative regulators of ciliogenesis), demonstrated by in vivo co-immunoprecipitation and direct interaction assays.","method":"Co-immunoprecipitation, direct interaction assay in vivo","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP demonstrated in single lab with multiple isoforms tested, but no reconstitution or mutagenesis","pmids":["26153462"],"is_preprint":false},{"year":2016,"finding":"Proteomic mass spectrometry of the mammalian katanin interaction network (Katan-ome) defined the protein interaction module for KATNAL2, placing it within the broader katanin family interaction network alongside KATNA1, KATNAL1, KATNB1, and KATNBL1.","method":"Mass spectrometry-based proteomics (affinity purification-MS) to define interaction modules","journal":"Molecular & cellular proteomics : MCP","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mass spectrometry interactome, single lab, network context established but KATNAL2-specific functional follow-up limited in this paper","pmids":["26929214"],"is_preprint":false},{"year":2017,"finding":"KATNAL2 is required in multiple aspects of mouse spermatogenesis: initiation of sperm tail growth from the basal body, sperm head shaping via the manchette, acrosome attachment, and sperm release. Depending on context, KATNAL2 can partner with the regulatory protein KATNB1 or act autonomously. Data indicate KATNAL2 may regulate δ- and ε-tubulin rather than classical α-β-tubulin microtubule polymers.","method":"Mouse knockout/loss-of-function with histological and cellular phenotypic readout; co-localization and interaction studies","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo mouse KO with multiple specific spermatogenic phenotypic readouts, partner interaction characterised, multiple orthogonal methods in single rigorous study","pmids":["29136647"],"is_preprint":false},{"year":2017,"finding":"KATNAL2 deletion in developing mouse neurons (via retroviral CRISPR-Cas9) results in decreased dendritic arborization.","method":"Retroviral CRISPR-Cas9 knockout in developing mouse neurons with morphological readout","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — CRISPR-Cas9 KO with specific cellular phenotype (dendritic arborization), single lab, single method","pmids":["27161796"],"is_preprint":false},{"year":2018,"finding":"In Xenopus embryos, Katnal2 localizes to basal bodies, ciliary axonemes, centrioles, and mitotic spindles. Knockdown of Katnal2 impairs ciliogenesis and brain development in vivo, and it is expressed broadly in ciliated and neurogenic tissues throughout embryonic development.","method":"Morpholino knockdown in Xenopus embryos; immunofluorescence localization; phenotypic analysis of cilia and brain development","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KD in a vertebrate model with multiple specific phenotypic readouts (ciliogenesis, brain development) and direct localization, replicating findings from mammalian cell studies","pmids":["30096282"],"is_preprint":false},{"year":2020,"finding":"In Tetrahymena, the Katnal2 ortholog (Kat2) has a tripartite domain organization (N-terminal LisH domain, linker, C-terminal AAA catalytic domain). The LisH-containing N-terminal fragment is required for proper subcellular localization to basal bodies and ciliary outer doublets, for dimerization, and for protein stability. Localization to microtubular structures is sensitive to levels of microtubule glutamylation.","method":"Domain deletion/truncation analysis, localization by fluorescence microscopy in Tetrahymena; dimerization and stability assays","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mutagenesis/truncation with localization and stability readouts in a ciliate ortholog; single lab","pmids":["31991798"],"is_preprint":false},{"year":2021,"finding":"δ- and ε-tubulin localize to the manchette during murine spermatogenesis and interact with KATNAL2, suggesting a non-centriolar function for KATNAL2 in regulating these noncanonical tubulin polymers.","method":"Co-localization and interaction studies during spermatogenesis (review/synthesis of experimental findings from primary studies)","journal":"Trends in cell biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — interaction and co-localization cited from prior experimental work, presented in a review context; mechanistic detail limited in this abstract","pmids":["33867233"],"is_preprint":false},{"year":2024,"finding":"Nonsense truncation of Katnal2 (Katnal2Δ17) in mice causes impaired spermatogenesis and cerebral ventriculomegaly associated with disrupted primary cilia and ependymal planar cell polarity, resulting in impaired cilia-generated CSF flow. Prefrontal pyramidal neurons in ventriculomegalic Katnal2Δ17 mice exhibit decreased excitatory drive and reduced high-frequency firing. Mice engineered with the ASD-associated KATNAL2 F244L missense variant recapitulate the ventriculomegaly phenotype.","method":"Constitutive mouse knockout (Katnal2Δ17), knock-in missense variant (F244L), histology, ependymal cilia/planar cell polarity analysis, CSF flow assays, electrophysiology","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple mouse models (KO and knock-in), multiple orthogonal methods (ciliary function, planar cell polarity, electrophysiology), mechanistic pathway established","pmids":["38916997"],"is_preprint":false},{"year":2024,"finding":"Katnal2 knockout mice display ASD-like social communication deficits and age-dependent progressive ventricular enlargements involving increased length and beating frequency of motile cilia on ependymal cells (ciliary hyperfunction). Katnal2-KO hippocampal neurons show progressive synaptic deficits correlated with ASD-like transcriptomic changes involving synaptic gene down-regulation. Early postnatal Katnal2 re-expression prevents ciliary, ventricular, and behavioral phenotypes in Katnal2-KO adults, establishing a causal relationship and developmental time window.","method":"Constitutive KO mouse model, behavioral assays, ependymal cilia beat frequency/length measurements, RNA-seq transcriptomics, rescue by early postnatal re-expression","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse with multiple orthogonal phenotypic readouts plus rescue experiment establishing causality; independent from PMID:38916997","pmids":["38718086"],"is_preprint":false},{"year":2025,"finding":"TUBD1 (delta tubulin) works in partnership with KATNAL2 and KATNB1 to regulate manchette remodeling and sperm head shaping in haploid spermatids, establishing KATNAL2 as a functional partner of delta tubulin in this specialized microtubule structure.","method":"Conditional TUBD1 knockout mouse model with phenotypic analysis of manchette and sperm head morphology; co-functional interaction inferred from genetic phenocopy","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO in vivo with specific phenotypic readouts, KATNAL2 functional partnership inferred from parallel phenotypes; single lab","pmids":["40586731"],"is_preprint":false}],"current_model":"KATNAL2 is a microtubule-severing AAA-ATPase (katanin family) that, through its LisH and AAA domains, localizes to centrioles, basal bodies, ciliary axonemes, mitotic spindles, and the manchette in spermatids, where it regulates cytokinesis, ciliogenesis (acting as a negative regulator of ependymal ciliary beat frequency and length), sperm head shaping, and neuronal dendritic arborization; it interacts with the regulatory subunit KATNB1, with centriolar proteins Nubp1/Nubp2, and with δ- and ε-tubulin, and loss-of-function in mice causes spermatogenic failure, cerebral ventriculomegaly via impaired ependymal planar cell polarity and CSF flow, and ASD-related synaptic and behavioral deficits."},"narrative":{"mechanistic_narrative":"KATNAL2 is a katanin-family AAA-ATPase that acts on microtubule-based structures to control cytokinesis, ciliogenesis, sperm differentiation, and neuronal morphogenesis [PMID:26153462, PMID:29136647, PMID:38916997]. It localizes to interphase microtubules, centrioles, the mitotic spindle, the midbody, and the basal body/axoneme of cilia, and loss of function in cultured cells causes inefficient cytokinesis, supernumerary centrioles, multipolar spindles, multinuclearity, increased microtubule acetylation, and strongly impaired ciliogenesis [PMID:26153462]. Domain dissection of the ciliate ortholog defines a tripartite architecture in which an N-terminal LisH domain mediates dimerization, protein stability, and localization to basal bodies and ciliary doublets, with targeting sensitive to microtubule glutamylation, while the C-terminal AAA domain provides catalytic activity [PMID:31991798]. In spermatogenesis KATNAL2 initiates sperm tail growth from the basal body, shapes the sperm head through the manchette, and supports acrosome attachment and sperm release, acting either with the regulatory subunit KATNB1 or autonomously, and operating on the noncanonical δ- and ε-tubulin polymers of the manchette together with TUBD1/KATNB1 [PMID:29136647, PMID:40586731]. In the nervous system KATNAL2 is required for dendritic arborization, and mouse models link its loss to cerebral ventriculomegaly arising from disrupted ependymal cilia and planar cell polarity with impaired CSF flow, alongside ASD-like synaptic, transcriptomic, and behavioral deficits; an ASD-associated F244L missense variant recapitulates ventriculomegaly, and early postnatal re-expression rescues the ciliary, ventricular, and behavioral phenotypes, establishing a defined developmental window [PMID:27161796, PMID:38916997, PMID:38718086]. KATNAL2 physically interacts with the centriolar P-loop NTPases Nubp1 and Nubp2 and sits within the broader katanin interaction network [PMID:26153462, PMID:26929214].","teleology":[{"year":2015,"claim":"Established KATNAL2 as a microtubule-associated factor whose isoforms decorate centrioles, spindle, midbody, and cilia and are required for faithful cytokinesis and ciliogenesis, defining its core cellular roles.","evidence":"shRNAi knockdown, stable overexpression, and immunofluorescence localization across five isoforms in cultured murine cells","pmids":["26153462"],"confidence":"High","gaps":["Does not demonstrate microtubule-severing biochemical activity directly","Does not resolve which isoform drives which phenotype","Mechanism linking KATNAL2 to centriole number control unknown"]},{"year":2015,"claim":"Identified centriolar P-loop NTPases Nubp1/Nubp2 as direct KATNAL2 partners, placing it among centriole-resident negative regulators of ciliogenesis.","evidence":"In vivo co-immunoprecipitation and direct interaction assays with multiple isoforms","pmids":["26153462"],"confidence":"Medium","gaps":["No reconstitution or interaction-mapping mutagenesis","Functional consequence of the interaction not tested","No reciprocal endogenous validation"]},{"year":2016,"claim":"Embedded KATNAL2 within the mammalian katanin interactome alongside KATNA1, KATNAL1, KATNB1, and KATNBL1, providing network context for its regulation.","evidence":"Affinity purification mass-spectrometry interactome (Katan-ome)","pmids":["26929214"],"confidence":"Medium","gaps":["KATNAL2-specific functional follow-up limited","Stoichiometry and direct vs indirect contacts not resolved"]},{"year":2017,"claim":"Demonstrated an in vivo requirement for KATNAL2 across distinct steps of spermatogenesis and pointed to δ-/ε-tubulin rather than canonical α-β polymers as its substrate, expanding katanin biology beyond classical microtubules.","evidence":"Mouse loss-of-function knockout with histological and cellular readouts plus co-localization/interaction studies","pmids":["29136647"],"confidence":"High","gaps":["Direct enzymatic action on δ-/ε-tubulin not biochemically shown","When KATNAL2 acts with KATNB1 versus autonomously not defined"]},{"year":2017,"claim":"Extended KATNAL2 function to neuronal development by showing it is needed for normal dendritic arborization.","evidence":"Retroviral CRISPR-Cas9 knockout in developing mouse neurons with morphological readout","pmids":["27161796"],"confidence":"Medium","gaps":["Single method/lab","Molecular mechanism linking microtubule severing to dendrite branching unknown"]},{"year":2018,"claim":"Confirmed conserved KATNAL2 localization and ciliogenesis/brain-development function in a second vertebrate, generalizing the mammalian cell findings to whole-organism development.","evidence":"Morpholino knockdown, immunofluorescence, and phenotypic analysis in Xenopus embryos","pmids":["30096282"],"confidence":"High","gaps":["Morpholino specificity not cross-validated genetically","Direct cause of brain phenotype (cilia vs neuron-intrinsic) not separated"]},{"year":2020,"claim":"Mapped the structural basis of KATNAL2 targeting, showing the LisH-containing N-terminus governs dimerization, stability, and localization, with glutamylation-sensitive recruitment.","evidence":"Domain truncation/deletion with localization, dimerization, and stability assays in Tetrahymena","pmids":["31991798"],"confidence":"Medium","gaps":["Ciliate ortholog may differ from mammalian protein","Catalytic AAA-domain activity not directly assayed","Glutamylation reader mechanism not defined"]},{"year":2021,"claim":"Consolidated the model that KATNAL2 regulates noncanonical δ-/ε-tubulin at the manchette, a non-centriolar microtubule structure.","evidence":"Co-localization and interaction findings synthesized in a review","pmids":["33867233"],"confidence":"Low","gaps":["Review synthesis rather than new primary data","Direct biochemical interaction with δ-/ε-tubulin not established here"]},{"year":2024,"claim":"Established a causal mechanistic pathway from KATNAL2 loss to cerebral ventriculomegaly via disrupted ependymal cilia, planar cell polarity, and CSF flow, with cortical electrophysiological deficits and recapitulation by the ASD-associated F244L variant.","evidence":"Constitutive knockout and F244L knock-in mice with histology, cilia/PCP analysis, CSF flow assays, and electrophysiology","pmids":["38916997"],"confidence":"High","gaps":["Molecular link between ciliary defect and neuronal excitability deficits unclear","Whether F244L is hypomorphic or dominant-negative not resolved"]},{"year":2024,"claim":"Defined a developmental time window for KATNAL2 function by showing KO causes ciliary hyperfunction, progressive synaptic and behavioral deficits, and that early postnatal re-expression rescues all phenotypes, proving causality.","evidence":"Constitutive KO mouse, behavioral assays, ependymal cilia beat-frequency/length measurements, RNA-seq, and rescue by re-expression","pmids":["38718086"],"confidence":"High","gaps":["Apparent ciliary hyperfunction here versus impaired ciliogenesis in cell studies not mechanistically reconciled","Cell-type responsible for behavioral rescue not pinpointed"]},{"year":2025,"claim":"Identified TUBD1 (delta tubulin) as a functional partner of KATNAL2 and KATNB1 in manchette remodeling and sperm head shaping, cementing the noncanonical-tubulin module in spermatids.","evidence":"Conditional TUBD1 knockout mouse with manchette/sperm-head phenotyping and inferred co-functional partnership","pmids":["40586731"],"confidence":"Medium","gaps":["Partnership inferred from phenocopy rather than direct biochemistry","Order of action within the KATNAL2-KATNB1-TUBD1 module unknown"]},{"year":null,"claim":"Direct biochemical demonstration of KATNAL2 microtubule-severing or ATPase activity, and reconciliation of its opposing ciliary phenotypes (impaired ciliogenesis in cells versus ependymal ciliary hyperfunction in vivo), remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No in vitro reconstitution of severing activity in the corpus","Substrate preference for δ-/ε-tubulin not biochemically proven","Mechanism switching between negative and positive ciliary regulation undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0,6]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,7]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[3]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0,5]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[0,5,6]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,5]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,5,8]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[3,10]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,8,9]}],"complexes":["katanin complex (with KATNB1)"],"partners":["KATNB1","NUBP1","NUBP2","TUBD1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8IYT4","full_name":"Katanin p60 ATPase-containing subunit A-like 2","aliases":["p60 katanin-like 2"],"length_aa":538,"mass_kda":61.3,"function":"Severs microtubules in vitro in an ATP-dependent manner. This activity may promote rapid reorganization of cellular microtubule arrays","subcellular_location":"Cytoplasm, cytoskeleton; Cytoplasm; Cytoplasm, cytoskeleton, spindle; Cytoplasm, cytoskeleton, spindle pole","url":"https://www.uniprot.org/uniprotkb/Q8IYT4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KATNAL2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/KATNAL2","total_profiled":1310},"omim":[{"mim_id":"614697","title":"KATANIN, p60 SUBUNIT, A-LIKE PROTEIN 2; KATNAL2","url":"https://www.omim.org/entry/614697"},{"mim_id":"209850","title":"AUTISM","url":"https://www.omim.org/entry/209850"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Intermediate filaments","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"choroid plexus","ntpm":11.7},{"tissue":"testis","ntpm":12.2}],"url":"https://www.proteinatlas.org/search/KATNAL2"},"hgnc":{"alias_symbol":["MGC33211","DKFZP667C165"],"prev_symbol":[]},"alphafold":{"accession":"Q8IYT4","domains":[{"cath_id":"-","chopping":"2-84","consensus_level":"high","plddt":82.5655,"start":2,"end":84},{"cath_id":"3.40.50.300","chopping":"230-420","consensus_level":"high","plddt":85.9469,"start":230,"end":420},{"cath_id":"1.10.8.60","chopping":"426-489_500-521","consensus_level":"high","plddt":90.2033,"start":426,"end":521}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IYT4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IYT4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IYT4-F1-predicted_aligned_error_v6.png","plddt_mean":71.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KATNAL2","jax_strain_url":"https://www.jax.org/strain/search?query=KATNAL2"},"sequence":{"accession":"Q8IYT4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IYT4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IYT4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IYT4"}},"corpus_meta":[{"pmid":"22495311","id":"PMC_22495311","title":"Patterns 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journal","url":"https://pubmed.ncbi.nlm.nih.gov/41910195","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16351,"output_tokens":2919,"usd":0.046419,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10279,"output_tokens":3961,"usd":0.07521,"stage2_stop_reason":"end_turn"},"total_usd":0.121629,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"KATNAL2 exists as a family of five alternatively spliced isoforms in mouse; these isoforms localize to interphase microtubules, centrioles, mitotic spindle, midbody, and the axoneme/basal body of sensory cilia. shRNAi knockdown causes inefficient cytokinesis, enlarged cells and nuclei, increased centriole numbers, aberrant multipolar mitotic spindles, chromosome bridges, multinuclearity, increased MT acetylation, and an altered cell cycle pattern. Silencing or stable overexpression of KATNAL2 isoforms drastically reduces ciliogenesis.\",\n      \"method\": \"shRNAi knockdown, stable overexpression, subcellular localization by immunofluorescence in cultured murine cells\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (KD, OE, localization), replicated across multiple isoforms with specific cellular phenotypic readouts in a single rigorous study\",\n      \"pmids\": [\"26153462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"KATNAL2 isoforms directly interact with nucleotide-binding proteins Nubp1 and Nubp2 (MRP/MinD-type P-loop NTPases that are integral centriole components and negative regulators of ciliogenesis), demonstrated by in vivo co-immunoprecipitation and direct interaction assays.\",\n      \"method\": \"Co-immunoprecipitation, direct interaction assay in vivo\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP demonstrated in single lab with multiple isoforms tested, but no reconstitution or mutagenesis\",\n      \"pmids\": [\"26153462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Proteomic mass spectrometry of the mammalian katanin interaction network (Katan-ome) defined the protein interaction module for KATNAL2, placing it within the broader katanin family interaction network alongside KATNA1, KATNAL1, KATNB1, and KATNBL1.\",\n      \"method\": \"Mass spectrometry-based proteomics (affinity purification-MS) to define interaction modules\",\n      \"journal\": \"Molecular & cellular proteomics : MCP\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mass spectrometry interactome, single lab, network context established but KATNAL2-specific functional follow-up limited in this paper\",\n      \"pmids\": [\"26929214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KATNAL2 is required in multiple aspects of mouse spermatogenesis: initiation of sperm tail growth from the basal body, sperm head shaping via the manchette, acrosome attachment, and sperm release. Depending on context, KATNAL2 can partner with the regulatory protein KATNB1 or act autonomously. Data indicate KATNAL2 may regulate δ- and ε-tubulin rather than classical α-β-tubulin microtubule polymers.\",\n      \"method\": \"Mouse knockout/loss-of-function with histological and cellular phenotypic readout; co-localization and interaction studies\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo mouse KO with multiple specific spermatogenic phenotypic readouts, partner interaction characterised, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"29136647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KATNAL2 deletion in developing mouse neurons (via retroviral CRISPR-Cas9) results in decreased dendritic arborization.\",\n      \"method\": \"Retroviral CRISPR-Cas9 knockout in developing mouse neurons with morphological readout\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — CRISPR-Cas9 KO with specific cellular phenotype (dendritic arborization), single lab, single method\",\n      \"pmids\": [\"27161796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In Xenopus embryos, Katnal2 localizes to basal bodies, ciliary axonemes, centrioles, and mitotic spindles. Knockdown of Katnal2 impairs ciliogenesis and brain development in vivo, and it is expressed broadly in ciliated and neurogenic tissues throughout embryonic development.\",\n      \"method\": \"Morpholino knockdown in Xenopus embryos; immunofluorescence localization; phenotypic analysis of cilia and brain development\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KD in a vertebrate model with multiple specific phenotypic readouts (ciliogenesis, brain development) and direct localization, replicating findings from mammalian cell studies\",\n      \"pmids\": [\"30096282\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In Tetrahymena, the Katnal2 ortholog (Kat2) has a tripartite domain organization (N-terminal LisH domain, linker, C-terminal AAA catalytic domain). The LisH-containing N-terminal fragment is required for proper subcellular localization to basal bodies and ciliary outer doublets, for dimerization, and for protein stability. Localization to microtubular structures is sensitive to levels of microtubule glutamylation.\",\n      \"method\": \"Domain deletion/truncation analysis, localization by fluorescence microscopy in Tetrahymena; dimerization and stability assays\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mutagenesis/truncation with localization and stability readouts in a ciliate ortholog; single lab\",\n      \"pmids\": [\"31991798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"δ- and ε-tubulin localize to the manchette during murine spermatogenesis and interact with KATNAL2, suggesting a non-centriolar function for KATNAL2 in regulating these noncanonical tubulin polymers.\",\n      \"method\": \"Co-localization and interaction studies during spermatogenesis (review/synthesis of experimental findings from primary studies)\",\n      \"journal\": \"Trends in cell biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — interaction and co-localization cited from prior experimental work, presented in a review context; mechanistic detail limited in this abstract\",\n      \"pmids\": [\"33867233\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Nonsense truncation of Katnal2 (Katnal2Δ17) in mice causes impaired spermatogenesis and cerebral ventriculomegaly associated with disrupted primary cilia and ependymal planar cell polarity, resulting in impaired cilia-generated CSF flow. Prefrontal pyramidal neurons in ventriculomegalic Katnal2Δ17 mice exhibit decreased excitatory drive and reduced high-frequency firing. Mice engineered with the ASD-associated KATNAL2 F244L missense variant recapitulate the ventriculomegaly phenotype.\",\n      \"method\": \"Constitutive mouse knockout (Katnal2Δ17), knock-in missense variant (F244L), histology, ependymal cilia/planar cell polarity analysis, CSF flow assays, electrophysiology\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple mouse models (KO and knock-in), multiple orthogonal methods (ciliary function, planar cell polarity, electrophysiology), mechanistic pathway established\",\n      \"pmids\": [\"38916997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Katnal2 knockout mice display ASD-like social communication deficits and age-dependent progressive ventricular enlargements involving increased length and beating frequency of motile cilia on ependymal cells (ciliary hyperfunction). Katnal2-KO hippocampal neurons show progressive synaptic deficits correlated with ASD-like transcriptomic changes involving synaptic gene down-regulation. Early postnatal Katnal2 re-expression prevents ciliary, ventricular, and behavioral phenotypes in Katnal2-KO adults, establishing a causal relationship and developmental time window.\",\n      \"method\": \"Constitutive KO mouse model, behavioral assays, ependymal cilia beat frequency/length measurements, RNA-seq transcriptomics, rescue by early postnatal re-expression\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse with multiple orthogonal phenotypic readouts plus rescue experiment establishing causality; independent from PMID:38916997\",\n      \"pmids\": [\"38718086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TUBD1 (delta tubulin) works in partnership with KATNAL2 and KATNB1 to regulate manchette remodeling and sperm head shaping in haploid spermatids, establishing KATNAL2 as a functional partner of delta tubulin in this specialized microtubule structure.\",\n      \"method\": \"Conditional TUBD1 knockout mouse model with phenotypic analysis of manchette and sperm head morphology; co-functional interaction inferred from genetic phenocopy\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO in vivo with specific phenotypic readouts, KATNAL2 functional partnership inferred from parallel phenotypes; single lab\",\n      \"pmids\": [\"40586731\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KATNAL2 is a microtubule-severing AAA-ATPase (katanin family) that, through its LisH and AAA domains, localizes to centrioles, basal bodies, ciliary axonemes, mitotic spindles, and the manchette in spermatids, where it regulates cytokinesis, ciliogenesis (acting as a negative regulator of ependymal ciliary beat frequency and length), sperm head shaping, and neuronal dendritic arborization; it interacts with the regulatory subunit KATNB1, with centriolar proteins Nubp1/Nubp2, and with δ- and ε-tubulin, and loss-of-function in mice causes spermatogenic failure, cerebral ventriculomegaly via impaired ependymal planar cell polarity and CSF flow, and ASD-related synaptic and behavioral deficits.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KATNAL2 is a katanin-family AAA-ATPase that acts on microtubule-based structures to control cytokinesis, ciliogenesis, sperm differentiation, and neuronal morphogenesis [#0, #3, #8]. It localizes to interphase microtubules, centrioles, the mitotic spindle, the midbody, and the basal body/axoneme of cilia, and loss of function in cultured cells causes inefficient cytokinesis, supernumerary centrioles, multipolar spindles, multinuclearity, increased microtubule acetylation, and strongly impaired ciliogenesis [#0]. Domain dissection of the ciliate ortholog defines a tripartite architecture in which an N-terminal LisH domain mediates dimerization, protein stability, and localization to basal bodies and ciliary doublets, with targeting sensitive to microtubule glutamylation, while the C-terminal AAA domain provides catalytic activity [#6]. In spermatogenesis KATNAL2 initiates sperm tail growth from the basal body, shapes the sperm head through the manchette, and supports acrosome attachment and sperm release, acting either with the regulatory subunit KATNB1 or autonomously, and operating on the noncanonical δ- and ε-tubulin polymers of the manchette together with TUBD1/KATNB1 [#3, #10]. In the nervous system KATNAL2 is required for dendritic arborization, and mouse models link its loss to cerebral ventriculomegaly arising from disrupted ependymal cilia and planar cell polarity with impaired CSF flow, alongside ASD-like synaptic, transcriptomic, and behavioral deficits; an ASD-associated F244L missense variant recapitulates ventriculomegaly, and early postnatal re-expression rescues the ciliary, ventricular, and behavioral phenotypes, establishing a defined developmental window [#4, #8, #9]. KATNAL2 physically interacts with the centriolar P-loop NTPases Nubp1 and Nubp2 and sits within the broader katanin interaction network [#1, #2].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Established KATNAL2 as a microtubule-associated factor whose isoforms decorate centrioles, spindle, midbody, and cilia and are required for faithful cytokinesis and ciliogenesis, defining its core cellular roles.\",\n      \"evidence\": \"shRNAi knockdown, stable overexpression, and immunofluorescence localization across five isoforms in cultured murine cells\",\n      \"pmids\": [\"26153462\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not demonstrate microtubule-severing biochemical activity directly\", \"Does not resolve which isoform drives which phenotype\", \"Mechanism linking KATNAL2 to centriole number control unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified centriolar P-loop NTPases Nubp1/Nubp2 as direct KATNAL2 partners, placing it among centriole-resident negative regulators of ciliogenesis.\",\n      \"evidence\": \"In vivo co-immunoprecipitation and direct interaction assays with multiple isoforms\",\n      \"pmids\": [\"26153462\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No reconstitution or interaction-mapping mutagenesis\", \"Functional consequence of the interaction not tested\", \"No reciprocal endogenous validation\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Embedded KATNAL2 within the mammalian katanin interactome alongside KATNA1, KATNAL1, KATNB1, and KATNBL1, providing network context for its regulation.\",\n      \"evidence\": \"Affinity purification mass-spectrometry interactome (Katan-ome)\",\n      \"pmids\": [\"26929214\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"KATNAL2-specific functional follow-up limited\", \"Stoichiometry and direct vs indirect contacts not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated an in vivo requirement for KATNAL2 across distinct steps of spermatogenesis and pointed to δ-/ε-tubulin rather than canonical α-β polymers as its substrate, expanding katanin biology beyond classical microtubules.\",\n      \"evidence\": \"Mouse loss-of-function knockout with histological and cellular readouts plus co-localization/interaction studies\",\n      \"pmids\": [\"29136647\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct enzymatic action on δ-/ε-tubulin not biochemically shown\", \"When KATNAL2 acts with KATNB1 versus autonomously not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended KATNAL2 function to neuronal development by showing it is needed for normal dendritic arborization.\",\n      \"evidence\": \"Retroviral CRISPR-Cas9 knockout in developing mouse neurons with morphological readout\",\n      \"pmids\": [\"27161796\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single method/lab\", \"Molecular mechanism linking microtubule severing to dendrite branching unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Confirmed conserved KATNAL2 localization and ciliogenesis/brain-development function in a second vertebrate, generalizing the mammalian cell findings to whole-organism development.\",\n      \"evidence\": \"Morpholino knockdown, immunofluorescence, and phenotypic analysis in Xenopus embryos\",\n      \"pmids\": [\"30096282\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Morpholino specificity not cross-validated genetically\", \"Direct cause of brain phenotype (cilia vs neuron-intrinsic) not separated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Mapped the structural basis of KATNAL2 targeting, showing the LisH-containing N-terminus governs dimerization, stability, and localization, with glutamylation-sensitive recruitment.\",\n      \"evidence\": \"Domain truncation/deletion with localization, dimerization, and stability assays in Tetrahymena\",\n      \"pmids\": [\"31991798\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ciliate ortholog may differ from mammalian protein\", \"Catalytic AAA-domain activity not directly assayed\", \"Glutamylation reader mechanism not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Consolidated the model that KATNAL2 regulates noncanonical δ-/ε-tubulin at the manchette, a non-centriolar microtubule structure.\",\n      \"evidence\": \"Co-localization and interaction findings synthesized in a review\",\n      \"pmids\": [\"33867233\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Review synthesis rather than new primary data\", \"Direct biochemical interaction with δ-/ε-tubulin not established here\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established a causal mechanistic pathway from KATNAL2 loss to cerebral ventriculomegaly via disrupted ependymal cilia, planar cell polarity, and CSF flow, with cortical electrophysiological deficits and recapitulation by the ASD-associated F244L variant.\",\n      \"evidence\": \"Constitutive knockout and F244L knock-in mice with histology, cilia/PCP analysis, CSF flow assays, and electrophysiology\",\n      \"pmids\": [\"38916997\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between ciliary defect and neuronal excitability deficits unclear\", \"Whether F244L is hypomorphic or dominant-negative not resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a developmental time window for KATNAL2 function by showing KO causes ciliary hyperfunction, progressive synaptic and behavioral deficits, and that early postnatal re-expression rescues all phenotypes, proving causality.\",\n      \"evidence\": \"Constitutive KO mouse, behavioral assays, ependymal cilia beat-frequency/length measurements, RNA-seq, and rescue by re-expression\",\n      \"pmids\": [\"38718086\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Apparent ciliary hyperfunction here versus impaired ciliogenesis in cell studies not mechanistically reconciled\", \"Cell-type responsible for behavioral rescue not pinpointed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified TUBD1 (delta tubulin) as a functional partner of KATNAL2 and KATNB1 in manchette remodeling and sperm head shaping, cementing the noncanonical-tubulin module in spermatids.\",\n      \"evidence\": \"Conditional TUBD1 knockout mouse with manchette/sperm-head phenotyping and inferred co-functional partnership\",\n      \"pmids\": [\"40586731\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Partnership inferred from phenocopy rather than direct biochemistry\", \"Order of action within the KATNAL2-KATNB1-TUBD1 module unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Direct biochemical demonstration of KATNAL2 microtubule-severing or ATPase activity, and reconciliation of its opposing ciliary phenotypes (impaired ciliogenesis in cells versus ependymal ciliary hyperfunction in vivo), remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro reconstitution of severing activity in the corpus\", \"Substrate preference for δ-/ε-tubulin not biochemically proven\", \"Mechanism switching between negative and positive ciliary regulation undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 7]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [0, 5, 6]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0005819\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 5, 8]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [3, 10]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 8, 9]}\n    ],\n    \"complexes\": [\"katanin complex (with KATNB1)\"],\n    \"partners\": [\"KATNB1\", \"NUBP1\", \"NUBP2\", \"TUBD1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}