Affinage

KATNAL2

Katanin p60 ATPase-containing subunit A-like 2 · UniProt Q8IYT4

Length
538 aa
Mass
61.3 kDa
Annotated
2026-04-28
28 papers in source corpus 10 papers cited in narrative 10 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KATNAL2 is a katanin-family AAA ATPase that regulates microtubule dynamics at centrioles, mitotic spindles, midbodies, basal bodies, and ciliary axonemes to control ciliogenesis, cytokinesis, cell cycle progression, spermatogenesis, and neuronal development. Knockdown or knockout causes multipolar spindles, multinuclearity, increased microtubule acetylation, impaired ciliogenesis, and defective dendritic arborization, while in vivo loss produces ciliopathy phenotypes including ventriculomegaly from disrupted ependymal cilia-driven CSF flow, male infertility from failed sperm head shaping and tail initiation, and decreased cortical neuronal excitatory drive (PMID:26153462, PMID:38916997, PMID:38718086, PMID:29136647). KATNAL2 partners with KATNB1 or acts autonomously depending on context, interacts with noncanonical δ- and ε-tubulins at the manchette during spermatogenesis, and requires its N-terminal LisH domain for dimerization, protein stability, and subcellular targeting to basal bodies and ciliary doublets (PMID:29136647, PMID:31991798, PMID:40586731). Loss-of-function mutations in KATNAL2 cause ASD-like social communication deficits and progressive ventricular enlargement in mice, phenotypes rescued by early postnatal re-expression, and an ASD-associated human missense variant (F244L) recapitulates ventriculomegaly in knock-in mice (PMID:38718086, PMID:38916997).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2015 High

    Establishing that KATNAL2 is a multi-isoform microtubule regulator essential for ciliogenesis and cell division resolved its broad cellular roles beyond a presumed severing enzyme.

    Evidence shRNAi knockdown in cultured murine cells with immunofluorescence, co-IP, and cell cycle analysis

    PMID:26153462

    Open questions at the time
    • Catalytic severing activity not directly demonstrated in vitro
    • Functional distinction among the five isoforms unclear
    • Relationship to known katanin regulatory subunits not defined
  2. 2016 Medium

    Placing KATNAL2 within the broader katanin interactome and showing KATNB1 competes for subunit interactions revealed a competitive regulatory network governing katanin activity.

    Evidence Mass spectrometry-based proteomic interaction mapping and co-IP

    PMID:26929214

    Open questions at the time
    • KATNAL2-specific binding partners within the network not individually validated
    • Whether KATNAL2 binds KATNB1 directly or indirectly not resolved in this study
    • Functional consequence of competition for KATNAL2 activity unknown
  3. 2016 Medium

    Demonstrating that KATNAL2 loss reduces dendritic arborization established a neuronal morphogenesis function, extending its role beyond dividing and ciliated cells.

    Evidence CRISPR-Cas9 knockout in developing mouse neurons with morphological analysis

    PMID:27161796

    Open questions at the time
    • Mechanism linking microtubule regulation to dendritic branching not identified
    • Not independently replicated at the time
    • In vivo neuronal consequences not assessed
  4. 2017 High

    Showing KATNAL2 is required for sperm tail initiation, head shaping via the manchette, acrosome attachment, and sperm release — and can act independently of KATNB1 — defined it as a central regulator of spermatogenesis with context-dependent partnerships.

    Evidence Mouse genetic knockout with co-IP, immunofluorescence, and electron microscopy

    PMID:29136647

    Open questions at the time
    • Enzymatic activity on δ/ε-tubulin versus α/β-tubulin not biochemically resolved
    • Structural basis for KATNB1-independent function unknown
    • Whether KATNAL2 severs or stabilizes manchette microtubules not distinguished
  5. 2018 High

    Cross-species validation in Xenopus confirmed that KATNAL2's roles in ciliogenesis and brain development are evolutionarily conserved, strengthening it as a core ciliary and neurodevelopmental factor.

    Evidence Morpholino knockdown in Xenopus embryos with localization and developmental phenotyping

    PMID:30096282

    Open questions at the time
    • Morpholino off-target effects not fully excluded
    • Mechanism of brain development defect not resolved
    • Rescue experiment not reported
  6. 2020 Medium

    Identifying the LisH domain as critical for dimerization, basal body targeting, and protein stability explained how KATNAL2 achieves subcellular specificity, and linked its localization to microtubule glutamylation levels.

    Evidence Domain truncation and mutagenesis with localization and stability assays in Tetrahymena

    PMID:31991798

    Open questions at the time
    • Whether glutamylation directly recruits KATNAL2 or acts indirectly not determined
    • LisH domain function not validated in mammalian cells
    • Structural basis of LisH-mediated dimerization not solved
  7. 2024 High

    Two independent mouse studies revealed that KATNAL2 loss causes ciliopathy with ventriculomegaly, disrupted ependymal planar cell polarity and CSF flow, decreased prefrontal neuronal excitatory drive, and ASD-like behavioral deficits — with an ASD-associated human variant recapitulating brain phenotypes and postnatal rescue proving causality.

    Evidence Germline KO mice, F244L knock-in mice, CSF flow assays, electrophysiology, behavioral testing, RNA-seq, and viral rescue

    PMID:38718086 PMID:38916997

    Open questions at the time
    • Whether ventriculomegaly is primarily from ciliary dysfunction or synaptic/neuronal defects not fully dissected
    • Molecular mechanism connecting KATNAL2 loss to altered cilia beating frequency (hyperfunction) versus ciliogenesis failure unclear
    • Human genetic studies confirming KATNAL2 as an ASD-causative gene are limited to single variant
  8. 2025 Medium

    Conditional TUBD1 knockout phenocopying aspects of KATNAL2 loss during spermatogenesis established that KATNAL2 operates in a functional complex with δ-tubulin and KATNB1 to remodel the manchette.

    Evidence Conditional TUBD1 knockout mouse with co-IP and co-localization of KATNAL2 and KATNB1

    PMID:40586731

    Open questions at the time
    • Direct biochemical activity of KATNAL2 on δ-tubulin not demonstrated
    • Stoichiometry and assembly mechanism of the KATNAL2–KATNB1–TUBD1 complex unknown
    • Whether this partnership operates outside spermatogenesis not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • The core enzymatic mechanism — whether KATNAL2 severs, depolymerizes, or stabilizes microtubules, and whether it directly acts on noncanonical tubulins — remains biochemically undefined, as does the structural basis for its context-dependent KATNB1 dependence.
  • No in vitro reconstitution of KATNAL2 microtubule-severing activity
  • No high-resolution structure of KATNAL2 or its complexes
  • Substrate specificity (α/β-tubulin polymers vs. δ/ε-tubulin) unresolved biochemically

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 3 GO:0140657 ATP-dependent activity 2
Localization
GO:0005815 microtubule organizing center 3 GO:0005856 cytoskeleton 3 GO:0005929 cilium 3
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-1852241 Organelle biogenesis and maintenance 4 R-HSA-1474165 Reproduction 2 R-HSA-1640170 Cell Cycle 1
Partners
KATNB1NUBP1NUBP2TUBD1

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 KATNAL2 exists as a family of five alternatively spliced isoforms in mouse that localize to interphase microtubules, centrioles, mitotic spindle, midbody, and 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, altered cell cycle pattern, and drastically reduced ciliogenesis. The isoforms interact with each other, with themselves, and directly with NTPases Nubp1 and Nubp2 (negative regulators of ciliogenesis and centriole duplication). shRNAi knockdown, co-immunoprecipitation, immunofluorescence localization, overexpression studies in cultured murine cells Cellular and molecular life sciences : CMLS High 26153462
2016 KATNAL2 is part of the mammalian katanin interactome (Katan-ome) as defined by mass spectrometry-based proteomics. KATNB1 (p80 regulatory subunit) can compete the interaction of KATNBL1 with KATNA1 and KATNAL1, placing KATNAL2 within a competitive regulatory network of katanin subunits. Mass spectrometry-based proteomic interaction mapping, Co-immunoprecipitation Molecular & cellular proteomics : MCP Medium 26929214
2016 CRISPR-Cas9 deletion of Katnal2 in developing mouse neurons results in decreased dendritic arborization, establishing a role for KATNAL2 in neuronal morphogenesis. Retroviral CRISPR-Cas9 knockout in developing mouse neurons with morphological phenotypic readout Scientific reports Medium 27161796
2017 KATNAL2 plays critical roles 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 regulatory protein KATNB1 or act autonomously. Evidence suggests KATNAL2 may regulate δ- and ε-tubulin rather than classical α-β-tubulin microtubule polymers. Mouse genetic knockout/loss-of-function model, co-immunoprecipitation, immunofluorescence, electron microscopy PLoS genetics High 29136647
2018 Katnal2 in Xenopus embryos is expressed broadly in ciliated and neurogenic tissues, localizes to basal bodies, ciliary axonemes, centrioles, and mitotic spindles, and is required for ciliogenesis and brain development in vivo. Morpholino knockdown in Xenopus embryos, immunofluorescence localization, phenotypic analysis of cilia and brain development Developmental biology High 30096282
2020 In Tetrahymena, the N-terminal LisH domain-containing fragment of Katnal2 (Kat2) is important for subcellular localization to basal bodies and ciliary outer doublets, dimerization, and protein stability. Co-localization with microtubular structures is sensitive to levels of microtubule glutamylation. Domain truncation/mutagenesis, immunofluorescence localization, protein stability assays in Tetrahymena Cells Medium 31991798
2021 δ- and ε-tubulin localize to the manchette during murine spermatogenesis and interact with KATNAL2, suggesting novel non-centriolar functions for both KATNAL2 and these noncanonical tubulins beyond classical α-β-tubulin microtubule regulation. Co-immunoprecipitation and immunolocalization in murine spermatogenic cells (review synthesizing primary data) Trends in cell biology Medium 33867233
2024 Nonsense truncation of Katnal2 (Katnal2Δ17) in mice causes ciliopathy phenotypes including impaired spermatogenesis and cerebral ventriculomegaly. KATNAL2 is highly expressed in ciliated radial glia of the fetal ventricular-subventricular zone, ependymal cells, and neurons. Loss of KATNAL2 disrupts primary cilia and ependymal planar cell polarity, impairing cilia-generated CSF flow and causing ventriculomegaly. Prefrontal pyramidal neurons show decreased excitatory drive and reduced high-frequency firing. An ASD-associated KATNAL2 F244L missense knock-in mouse recapitulates ventriculomegaly. Germline knockout mouse (Katnal2Δ17), knock-in mouse (F244L), immunofluorescence, CSF flow assays, electrophysiology, human patient variant analysis Proceedings of the National Academy of Sciences of the United States of America High 38916997
2024 Katnal2 knockout in mice causes ASD-like social communication deficits and age-dependent progressive ventricular enlargement associated with increased length and beating frequency of motile cilia on ependymal cells (ciliary hyperfunction). Katnal2-KO hippocampal neurons show progressive synaptic deficits correlating with ASD-like transcriptomic changes (synaptic gene down-regulation). Early postnatal Katnal2 re-expression prevents ciliary, ventricular, and behavioral phenotypes, establishing a causal relationship. Knockout mouse model, cilia beating frequency measurement, behavioral assays, electrophysiology, RNA-seq transcriptomics, viral rescue (postnatal re-expression) PLoS biology High 38718086
2025 TUBD1 (delta tubulin) works in partnership with KATNAL2 and KATNB1 to regulate manchette remodeling and sperm head shaping in haploid male germ cells, as shown by conditional TUBD1 knockout mice where spermatogenesis defects phenocopy aspects of KATNAL2 loss. Conditional knockout mouse (TUBD1), co-immunoprecipitation/co-localization with KATNAL2 and KATNB1, immunofluorescence, electron microscopy The Journal of cell biology Medium 40586731

Source papers

Stage 0 corpus · 28 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 1337 22495311
2010 Meta-analysis of genome-wide association studies for personality. Molecular psychiatry 188 21173776
2017 Katanin-like 2 (KATNAL2) functions in multiple aspects of haploid male germ cell development in the mouse. PLoS genetics 52 29136647
2020 A systems biology framework integrating GWAS and RNA-seq to shed light on the molecular basis of sperm quality in swine. Genetics, selection, evolution : GSE 44 33292187
2016 Proteomic Analysis of the Mammalian Katanin Family of Microtubule-severing Enzymes Defines Katanin p80 subunit B-like 1 (KATNBL1) as a Regulator of Mammalian Katanin Microtubule-severing. Molecular & cellular proteomics : MCP 42 26929214
2016 A Retroviral CRISPR-Cas9 System for Cellular Autism-Associated Phenotype Discovery in Developing Neurons. Scientific reports 39 27161796
2012 Genome-wide methylation profiling identifies hypermethylated biomarkers in high-grade cervical intraepithelial neoplasia. Epigenetics 39 23018867
2021 Novel Recurrent Altered Genes in Chinese Patients With Anaplastic Thyroid Cancer. The Journal of clinical endocrinology and metabolism 35 33428730
2018 Katanin-like protein Katnal2 is required for ciliogenesis and brain development in Xenopus embryos. Developmental biology 33 30096282
2015 Penetrance of pathogenic mutations in haploinsufficient genes for intellectual disability and related disorders. European journal of medical genetics 31 26506440
2015 A novel family of katanin-like 2 protein isoforms (KATNAL2), interacting with nucleotide-binding proteins Nubp1 and Nubp2, are key regulators of different MT-based processes in mammalian cells. Cellular and molecular life sciences : CMLS 30 26153462
2012 Dilution of candidates: the case of iron-related genes in restless legs syndrome. European journal of human genetics : EJHG 24 22929029
2011 Search for inherited susceptibility to radiation-associated meningioma by genomewide SNP linkage disequilibrium mapping. British journal of cancer 23 21364586
2021 Delta and epsilon tubulin in mammalian development. Trends in cell biology 21 33867233
2024 Genetic etiological spectrum of sperm morphological abnormalities. Journal of assisted reproduction and genetics 12 39417902
2010 Sperm mitochondria diaphorase activity--a gene mapping study of recombinant inbred strains of mice. The International journal of developmental biology 10 20209439
2020 The LisH Domain-Containing N-Terminal Fragment is Important for the Localization, Dimerization, and Stability of Katnal2 in Tetrahymena. Cells 9 31991798
2022 Contribution of copy number variations to the risk of severe eating disorders. Psychiatry and clinical neurosciences 8 35611833
2020 Whole-Exome Sequencing of Discordant Monozygotic Twin Families for Identification of Candidate Genes for Microtia-Atresia. Frontiers in genetics 8 33193662
2018 Genetic influences on creativity: an exploration of convergent and divergent thinking. PeerJ 8 30083479
2024 Loss of Katnal2 leads to ependymal ciliary hyperfunction and autism-related phenotypes in mice. PLoS biology 6 38718086
2024 Pathogenic variants in autism gene KATNAL2 cause hydrocephalus and disrupt neuronal connectivity by impairing ciliary microtubule dynamics. Proceedings of the National Academy of Sciences of the United States of America 6 38916997
2024 Elucidating genetic and molecular basis of altered higher-order brain structure-function coupling in major depressive disorder. NeuroImage 5 38971483
2025 Delta tubulin stabilizes male meiotic kinetochores and aids microtubule remodeling and fertility. The Journal of cell biology 1 40586731
2025 Single-cell and multi-omics analysis identifies TRIM9 as a key ubiquitination regulator in pancreatic cancer. Frontiers in immunology 1 41050689
2024 Assessment of Probiotics' Impact on Neurodevelopmental and Behavioral Responses in Zebrafish Models: Implications for Autism Spectrum Disorder Therapy. Probiotics and antimicrobial proteins 1 39090455
2021 Investigation the Relationship of Autism Spectrum Disorder and FOXP2, GRIN2B, KATNAL2, GABRA4 Genes. Noro psikiyatri arsivi 1 34526837
2026 Fecal microbiota transplantation and Akkermansia muciniphila restore neurodevelopment and behavior via the gut-brain axis in autism-like zebrafish. The ISME journal 0 41910195