{"gene":"ANK2","run_date":"2026-06-09T22:02:43","timeline":{"discoveries":[{"year":2007,"finding":"ANK2 loss-of-function variants in cardiomyocytes cause a spectrum of cellular phenotypes ranging from wild-type activity to severe loss-of-function, with the severity correlating with clinical arrhythmia phenotype. Ankyrin-B-dependent protein interactions regulate cardiac electrogenesis.","method":"Primary cardiomyocyte assays with 9 nonsynonymous ANK2 variants; loss-of-function characterization","journal":"Circulation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean cellular loss-of-function assays with multiple variants, single lab, direct phenotypic readouts in cardiomyocytes","pmids":["17242276"],"is_preprint":false},{"year":2019,"finding":"Giant ankyrin-B (the neurospecific alternatively spliced ANK2 isoform) localizes to periodic axonal plasma membrane domains through L1 cell-adhesion molecule and couples microtubules to the plasma membrane, thereby preventing microtubule entry into nascent axon branches and limiting axon branching.","method":"Mouse model of human ASD mutation; cultured neuron branching assays; live imaging; genetic loss-of-function; behavioral analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal functional interaction established with L1-CAM, multiple orthogonal methods (imaging, genetics, behavior), replicated across conditions","pmids":["31285321"],"is_preprint":false},{"year":2024,"finding":"Ankyrin-B is essential for scaffolding NaV1.2 (encoded by SCN2A) to the dendritic membrane of neocortical pyramidal neurons; Ank2 haploinsufficiency phenocopies intrinsic dendritic excitability and synaptic deficits seen in Scn2a+/- neurons, establishing a direct convergent link between these two ASD risk genes.","method":"Mouse conditional knockout (Ank2 haploinsufficiency); electrophysiology; immunofluorescence localization of NaV1.2 in dendrites","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined cellular phenotype, direct localization experiment with functional consequence, phenocopy epistasis between two genes","pmids":["38290518"],"is_preprint":false},{"year":2017,"finding":"ANK2 variant p.S646F (in the membrane-binding domain) causes reduced ankyrin-B expression in H9c2 cells and aberrant cardiomyocyte localization, and results in loss of normal membrane targeting of the Na/Ca exchanger (a known ankyrin-B binding partner), identifying the membrane-binding domain as critical for ankyrin-B function.","method":"Bacterial expression for folding assessment; H9c2 cell expression; primary cardiomyocyte localization assays; immunofluorescence of Na/Ca exchanger targeting","journal":"Circulation. Cardiovascular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional consequence, multiple cell-based methods, single lab","pmids":["28196901"],"is_preprint":false},{"year":2023,"finding":"Ank2 knockout restricted to cortical and hippocampal excitatory neurons reduces total levels and density of Kv7.2/KCNQ2 and Kv7.3/KCNQ3 potassium channels at the axon initial segment (AIS) and causes elongated AIS, resulting in abnormally increased neuronal excitability and seizure-related death; Kv7 agonist retigabine rescues these phenotypes.","method":"Conditional knockout mice (Ank2-cKO); electrophysiology; immunofluorescence of AIS markers and Kv7 channels; pharmacological rescue with retigabine","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean conditional KO with defined cellular and in vivo phenotype, direct AIS localization data, pharmacological rescue, multiple orthogonal methods","pmids":["37321992"],"is_preprint":false},{"year":2023,"finding":"ANK2 loss-of-function in hiPSC-derived neurons produces hyperactive and desynchronized neuronal network activity (measured by MEA), increased somatodendritic complexity, altered axon initial segment (AIS) structure, and impaired activity-dependent AIS plasticity.","method":"CRISPR/Cas9 heterozygous ANK2 LoF allele in hiPSCs; differentiation to excitatory neurons; micro-electrode array (MEA) electrophysiology; morphological characterization of AIS","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — CRISPR-engineered human neuronal model, MEA functional readout, AIS structural analysis, multiple orthogonal methods in single study","pmids":["37195288"],"is_preprint":false},{"year":2023,"finding":"Prenatal (but not adolescent) deletion of Ank2 in cortical excitatory neurons and oligodendrocytes causes spontaneous seizures, network hyperexcitability/hypersynchrony, and upregulation of dendritic spine plasticity-regulatory proteins and downregulation of intermediate filaments at synaptic membranes. Ankyrin-B interactome contains autism/epilepsy risk factors and synaptic proteins. AMPA receptor antagonist perampanel restores cortical activity.","method":"Conditional knockout mice (Ank2-/-:Emx1-Cre vs Ank2-/-:CaMKIIα-Cre); calcium imaging of cortical slices; quantitative proteomic analysis of synaptic membranes; interactome characterization; pharmacological rescue","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple conditional KO models, calcium imaging, quantitative proteomics of synaptic membranes, interactome, pharmacological rescue — multiple orthogonal methods","pmids":["37428632"],"is_preprint":false},{"year":2019,"finding":"ANK2 variant p.L1622I displays reduced posttranslational expression in vivo, resulting in reduced cardiac ankyrin-B expression and reduced association with the Na/Ca exchanger binding partner; knock-in mice show arrhythmias, action potential duration increases, and afterdepolarizations.","method":"Knock-in mouse model; co-immunoprecipitation for Na/Ca exchanger association; in vivo electrophysiology; cellular action potential recordings","journal":"Heart rhythm","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knock-in animal model with defined in vivo and cellular phenotypes, Co-IP for binding partner, single lab","pmids":["27298202"],"is_preprint":false},{"year":2019,"finding":"ANK2-E1813K diminishes currents mediated by combined wild-type and H562R KCNH2 subunits in Xenopus oocytes, indicating that ANK2 functionally interacts with KCNH2 (hERG) to modulate potassium channel current and QT interval duration.","method":"Voltage-clamp recordings in Xenopus oocytes with co-expression of ANK2 C-terminal regulatory domain and KCNH2 constructs; HEK293 trafficking assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro electrophysiology reconstitution in Xenopus oocytes, single lab, limited to C-terminal domain of ANK2","pmids":["30929919"],"is_preprint":false},{"year":2019,"finding":"ANK2 (Ser3781) phosphorylation is dramatically reduced (>300-fold) in brains of PINK1-KO+A53T-SNCA mice, and ANK2/MAP1B expression depends on PINK1 levels, linking ANK2 post-translational phosphorylation to the PINK1/Parkin pathway.","method":"Quantitative label-free global phosphoproteomic mass spectrometry of mouse brain hemispheres; western blot validation of ANK2/MAP1B expression relative to PINK1 levels","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative phosphoproteomics plus western blot validation, in vivo mouse model, single lab","pmids":["31277379"],"is_preprint":false},{"year":2019,"finding":"ANK2 translation occurs specifically after nuclear envelope breakdown in mouse oocytes, with Ank2.3 mRNA localizing to the forming spindle; prevention of ANK2 translation causes cytokinesis abnormalities in oocytes. The 5'UTR contains an oligo-pyrimidine motif determining cap-dependent translation.","method":"mRNA localization in oocytes; translation inhibition experiments; cytokinesis phenotype quantification; 5'UTR motif analysis","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional consequence (cytokinesis defect upon translation inhibition), single lab, two methods","pmids":["31511568"],"is_preprint":false},{"year":2022,"finding":"ANK2 regulates neural stem cell differentiation and neuronal migration in the embryonic cerebral cortex; Ank2 knockdown via in utero electroporation alters expression of genes involved in neural development.","method":"In utero electroporation knockdown in mouse embryonic cerebral cortex; immunofluorescence; gene expression analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct loss-of-function in vivo with cellular phenotype (migration, differentiation), single lab, single primary method","pmids":["35313230"],"is_preprint":false},{"year":2025,"finding":"ANK2 deficiency induces mitochondrial cristae disorganization and membrane hyperpolarization, leading to bioenergetic stress and activation of the mitochondrial antiviral-signaling protein (MAVS); MAVS oligomerization enhances IL-6/IL-8 secretion, establishing an ANK2-MAVS-IL-8 axis connecting mitochondrial dysfunction to vascular inflammation.","method":"ANK2 knockdown cellular models; multi-omics (RNA-seq, proteomics, metabolomics, ATAC-seq); mitochondrial morphology and membrane potential assays; cytokine secretion measurement","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multi-omics plus functional assays in knockdown model, single lab, multiple orthogonal approaches","pmids":["41248744"],"is_preprint":false},{"year":2025,"finding":"USP46 stabilizes ANK2 protein by deubiquitination (preventing its degradation), and elevated ANK2 in hypoxia/reoxygenation-treated cardiomyocytes promotes apoptosis, inflammation, and ferroptosis; USP46 knockdown reduces ANK2 and alleviates myocardial injury in rats.","method":"Cycloheximide chase assay; ubiquitination assay; siRNA knockdown; flow cytometry for apoptosis; in vivo rat I/R model","journal":"Journal of biochemical and molecular toxicology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cycloheximide chase and ubiquitination assay directly demonstrate USP46-mediated deubiquitination of ANK2, single lab","pmids":["40878243"],"is_preprint":false},{"year":2025,"finding":"AlphaFold modeling and mutagenesis identified a pocket in the ANK2 membrane-binding domain that engages NrCAM at the conserved FIGQY cytoplasmic motif, and key interactions between the ANK2 spectrin-binding domain and β2-Spectrin repeats 14-15. ASD missense mutation AnkB A368G (NrCAM binding pocket) disrupted NrCAM association and impaired Semaphorin 3F-induced spine pruning in cortical neurons; AnkB R977Q disrupted β2-Spectrin association.","method":"AlphaFold structural modeling; co-immunoprecipitation from HEK293 cells with mutant constructs; cortical neuron spine pruning assay","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — structure-guided mutagenesis validated by Co-IP and neuronal functional assay, preprint, single lab","pmids":[],"is_preprint":true},{"year":2024,"finding":"Ankyrin-B and NrCAM mediate perisomatic synaptic contact between CCK basket interneurons and pyramidal neurons in mouse mPFC; deletion of Ankyrin-B from pyramidal neurons (via Nex1Cre-ERT2:Ank2flox/flox) decreases CCK-BC synaptic puncta on PN soma, while PV-BC contacts are unaffected.","method":"Conditional knockout (Nex1Cre-ERT2:Ank2flox/flox); immunolabeling for CCK-BC and PV-BC synaptic markers (VGLUT3, VGAT); CCK-BC reporter mouse (tdT at Sncg locus)","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean conditional KO with cell-type specific synaptic phenotype, multiple marker controls, preprint, single lab","pmids":[],"is_preprint":true},{"year":2026,"finding":"PTBP2 splicing regulator controls ANK2 exon 36 inclusion; loss of PTBP2 promotes near-complete inclusion of ANK2 exon 36, and this isoform switch is mechanistically required for RPE-to-neuron conversion — loss of exon 36 impairs neuronal induction, and re-expression of the exon-36-containing isoform restores conversion efficiency.","method":"PTBP2 knockdown in hRPE-19 cells; transcriptomic and splicing analysis; functional rescue assays with ANK2 exon 36 isoform","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional rescue assay establishes isoform-specific mechanism, single lab, transcriptomic validation","pmids":["41555757"],"is_preprint":false}],"current_model":"Ankyrin-B (ANK2) is a multifunctional scaffolding protein that recruits and stabilizes ion channels (NaV1.2, Na/Ca exchanger, KCNH2, Kv7.2/3), transporters, and cell adhesion molecules (L1-CAM, NrCAM) to specialized membrane domains in cardiomyocytes and neurons via its membrane-binding and spectrin-binding domains; in the heart, loss of ankyrin-B disrupts Na/Ca exchanger targeting and causes arrhythmias, while in neurons the giant brain isoform couples microtubules to the axonal plasma membrane through L1-CAM to limit axon branching, scaffolds NaV1.2 to dendritic membranes, and maintains Kv7 channel density at the axon initial segment to control excitability — with USP46-mediated deubiquitination stabilizing ANK2 protein and PINK1-dependent phosphorylation at Ser3781 modulating its function."},"narrative":{"mechanistic_narrative":"Ankyrin-B (ANK2) is a multifunctional membrane scaffolding protein that recruits and stabilizes ion channels, transporters, and cell adhesion molecules at specialized plasma membrane domains in both cardiomyocytes and neurons [PMID:28196901, PMID:38290518]. In the heart, ankyrin-B engages the Na/Ca exchanger through its membrane-binding domain, and loss-of-function variants that reduce ankyrin-B expression or membrane targeting disrupt Na/Ca exchanger localization and produce arrhythmias, action potential prolongation, and afterdepolarizations [PMID:17242276, PMID:28196901, PMID:27298202]; it also functionally modulates the KCNH2 (hERG) potassium channel current [PMID:30929919]. In the nervous system, the giant neurospecific isoform localizes to periodic axonal membrane domains via the L1 cell-adhesion molecule and couples microtubules to the plasma membrane, thereby restricting microtubule entry into nascent branches and limiting axon branching [PMID:31285321]. Ankyrin-B scaffolds NaV1.2 (SCN2A) to dendritic membranes of neocortical pyramidal neurons, converging functionally with SCN2A as an autism risk gene [PMID:38290518], and maintains Kv7.2/Kv7.3 (KCNQ2/KCNQ3) channel density and normal axon initial segment structure, with its loss causing AIS elongation, network hyperexcitability, and seizure-related death that is rescued by the Kv7 agonist retigabine [PMID:37321992, PMID:37195288, PMID:37428632]. Through NrCAM binding at a defined membrane-binding-domain pocket and β2-spectrin engagement via its spectrin-binding domain, ankyrin-B mediates Semaphorin 3F–dependent spine pruning and perisomatic CCK basket interneuron synaptic contacts onto pyramidal neurons. ANK2 also functions in cortical neural stem cell differentiation and neuronal migration [PMID:35313230] and in oocyte cytokinesis, where its spindle-localized isoform is translated after nuclear envelope breakdown [PMID:31511568]. ANK2 protein levels are controlled post-translationally by USP46-mediated deubiquitination [PMID:40878243] and by PINK1-dependent Ser3781 phosphorylation [PMID:31277379], and isoform identity is governed by PTBP2-regulated exon 36 splicing [PMID:41555757].","teleology":[{"year":2007,"claim":"Established that ANK2 variants causing graded cellular loss-of-function map onto clinical arrhythmia severity, framing ankyrin-B as a dose-sensitive regulator of cardiac electrogenesis.","evidence":"Primary cardiomyocyte assays of 9 nonsynonymous ANK2 variants","pmids":["17242276"],"confidence":"Medium","gaps":["Did not resolve which molecular interactions each variant disrupts","Mechanism linking expression level to electrical phenotype not defined"]},{"year":2017,"claim":"Localized ankyrin-B function to its membrane-binding domain by showing a domain variant reduces expression and abolishes Na/Ca exchanger membrane targeting.","evidence":"H9c2 and primary cardiomyocyte expression/localization assays with p.S646F","pmids":["28196901"],"confidence":"Medium","gaps":["Single lab, cell-based only","Did not test in vivo cardiac consequences of this variant"]},{"year":2019,"claim":"Demonstrated the giant neuronal isoform couples microtubules to the axonal membrane via L1-CAM to limit axon branching, defining a neuronal cytoskeleton-membrane scaffolding role distinct from cardiac function.","evidence":"Mouse ASD-mutation model, neuron branching assays, live imaging, behavior","pmids":["31285321"],"confidence":"High","gaps":["Did not address dendritic or AIS roles","Branching mechanism in vivo circuit consequences incomplete"]},{"year":2019,"claim":"Confirmed in vivo that a destabilizing variant lowers cardiac ankyrin-B and Na/Ca exchanger association, causing arrhythmia and afterdepolarizations, linking protein stability to electrical phenotype.","evidence":"p.L1622I knock-in mouse, Co-IP, in vivo and cellular electrophysiology","pmids":["27298202"],"confidence":"Medium","gaps":["Single lab","Mechanism of reduced posttranslational stability not defined"]},{"year":2019,"claim":"Extended ankyrin-B channel partnerships by showing functional interaction with KCNH2 (hERG) affecting potassium current and QT duration.","evidence":"Voltage-clamp in Xenopus oocytes with ANK2 C-terminal domain; HEK293 trafficking","pmids":["30929919"],"confidence":"Medium","gaps":["Limited to C-terminal domain reconstitution","No native cardiomyocyte validation"]},{"year":2019,"claim":"Connected ANK2 to a neurodegeneration pathway by identifying PINK1-dependent Ser3781 phosphorylation and PINK1-dependent ANK2 expression.","evidence":"Quantitative brain phosphoproteomics and western blot in PINK1-KO+A53T-SNCA mice","pmids":["31277379"],"confidence":"Medium","gaps":["Functional consequence of Ser3781 phosphorylation unknown","Direct vs indirect link to PINK1 not resolved"]},{"year":2019,"claim":"Revealed a non-neuronal, non-cardiac role: spindle-localized ANK2 translation after nuclear envelope breakdown is required for oocyte cytokinesis.","evidence":"Oocyte mRNA localization, translation inhibition, cytokinesis phenotype, 5'UTR motif analysis","pmids":["31511568"],"confidence":"Medium","gaps":["Molecular partners at the spindle not identified","Mechanism of cytokinesis defect undefined"]},{"year":2022,"claim":"Implicated ANK2 in early cortical development through control of neural stem cell differentiation and neuronal migration.","evidence":"In utero electroporation knockdown, immunofluorescence, gene expression analysis","pmids":["35313230"],"confidence":"Medium","gaps":["Single primary method","Direct molecular effectors of migration not defined"]},{"year":2023,"claim":"Defined ankyrin-B as a maintainer of Kv7.2/Kv7.3 density and AIS structure, with loss causing hyperexcitability and seizure death rescuable by a Kv7 agonist.","evidence":"Conditional Ank2-cKO mice, electrophysiology, AIS immunofluorescence, retigabine rescue","pmids":["37321992"],"confidence":"High","gaps":["Direct ankyrin-B/Kv7 binding interface not mapped","Whether AIS elongation is cause or consequence unresolved"]},{"year":2023,"claim":"Validated ANK2 LoF phenotypes in a human neuronal model, showing network hyperactivity, altered AIS structure, and impaired activity-dependent AIS plasticity.","evidence":"CRISPR heterozygous LoF hiPSC-derived neurons, MEA, AIS morphology","pmids":["37195288"],"confidence":"High","gaps":["Molecular driver of impaired AIS plasticity not identified","Channel-level mechanism in human neurons not dissected"]},{"year":2023,"claim":"Showed developmental-timing dependence of ANK2 loss and identified a synaptic interactome plus pharmacological rescue, linking ankyrin-B to network hypersynchrony.","evidence":"Multiple conditional KO mice, calcium imaging, synaptic membrane proteomics, perampanel rescue","pmids":["37428632"],"confidence":"High","gaps":["Direct vs indirect membership of interactome partners not all validated","Mechanism of intermediate filament downregulation unclear"]},{"year":2024,"claim":"Established convergence of two ASD risk genes by showing ankyrin-B scaffolds NaV1.2 to dendritic membranes and Ank2 haploinsufficiency phenocopies Scn2a loss.","evidence":"Conditional KO mice, dendritic electrophysiology, NaV1.2 immunolocalization","pmids":["38290518"],"confidence":"High","gaps":["Direct ankyrin-B/NaV1.2 binding interface not defined here","Whether convergence extends to synaptic deficits mechanistically incomplete"]},{"year":2024,"claim":"Identified a cell-type-specific synaptic role: ankyrin-B and NrCAM mediate CCK basket interneuron perisomatic contacts onto pyramidal neurons.","evidence":"Conditional KO, CCK-BC/PV-BC synaptic marker immunolabeling, reporter mouse (preprint)","pmids":[],"confidence":"Medium","gaps":["Preprint, single lab","Direct molecular requirement of NrCAM binding not separated from ankyrin-B loss"]},{"year":2025,"claim":"Mapped the structural basis for ankyrin-B partner binding, defining an NrCAM-engaging pocket and β2-spectrin interface and linking an ASD mutation to disrupted Sema3F-dependent spine pruning.","evidence":"AlphaFold modeling, mutagenesis Co-IP from HEK293, cortical neuron spine pruning assay (preprint)","pmids":[],"confidence":"Medium","gaps":["Preprint, single lab","Structural model not experimentally validated by direct structure"]},{"year":2025,"claim":"Defined post-translational control of ankyrin-B abundance via USP46 deubiquitination and linked elevated ANK2 to cardiomyocyte injury.","evidence":"Cycloheximide chase, ubiquitination assay, siRNA knockdown, rat I/R model","pmids":["40878243"],"confidence":"Medium","gaps":["Single lab","Direct vs indirect USP46-ANK2 enzyme-substrate relationship in vivo not fully resolved"]},{"year":2025,"claim":"Connected ankyrin-B deficiency to mitochondrial dysfunction and MAVS-driven vascular inflammation, expanding its role beyond membrane scaffolding.","evidence":"ANK2 knockdown, multi-omics, mitochondrial morphology/potential assays, cytokine measurement","pmids":["41248744"],"confidence":"Medium","gaps":["Mechanism linking ankyrin-B to mitochondrial cristae unknown","Whether effect is direct or secondary not established"]},{"year":2026,"claim":"Showed PTBP2-controlled ANK2 exon 36 splicing dictates an isoform required for RPE-to-neuron conversion, establishing isoform-specific functional identity.","evidence":"PTBP2 knockdown, splicing/transcriptomics, exon 36 isoform rescue in hRPE-19 cells","pmids":["41555757"],"confidence":"Medium","gaps":["Functional protein-level difference of exon 36 isoform not biochemically defined","Relevance to in vivo neurogenesis unaddressed"]},{"year":null,"claim":"How distinct ankyrin-B isoforms, their domain-specific partner repertoires, and post-translational regulators are coordinated to produce tissue-specific outcomes across heart, brain, mitochondria, and dividing cells remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified map linking isoform/domain to partner selection across tissues","Functional roles of identified phosphorylation/ubiquitination sites not causally tested","Mitochondrial and cell-division roles lack defined molecular mechanism"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,2,3,14]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[1,14]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,2,3]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[1]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[12]}],"pathway":[],"complexes":[],"partners":["L1CAM","SCN2A","SLC8A1","KCNH2","KCNQ2","KCNQ3","NRCAM","SPTBN1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q01484","full_name":"Ankyrin-2","aliases":["Ankyrin-B","Brain ankyrin","Non-erythroid ankyrin"],"length_aa":3957,"mass_kda":433.7,"function":"Plays an essential role in the localization and membrane stabilization of ion transporters and ion channels in several cell types, including cardiomyocytes, as well as in striated muscle cells. In skeletal muscle, required for proper localization of DMD and DCTN4 and for the formation and/or stability of a special subset of microtubules associated with costameres and neuromuscular junctions. In cardiomyocytes, required for coordinate assembly of Na/Ca exchanger, SLC8A1/NCX1, Na/K ATPases ATP1A1 and ATP1A2 and inositol 1,4,5-trisphosphate (InsP3) receptors at sarcoplasmic reticulum/sarcolemma sites. Required for expression and targeting of SPTBN1 in neonatal cardiomyocytes and for the regulation of neonatal cardiomyocyte contraction rate (PubMed:12571597). In the inner segment of rod photoreceptors, required for the coordinated expression of the Na/K ATPase, Na/Ca exchanger and beta-2-spectrin (SPTBN1) (By similarity). Plays a role in endocytosis and intracellular protein transport. Associates with phosphatidylinositol 3-phosphate (PI3P)-positive organelles and binds dynactin to promote long-range motility of cells. Recruits RABGAP1L to (PI3P)-positive early endosomes, where RABGAP1L inactivates RAB22A, and promotes polarized trafficking to the leading edge of the migrating cells. Part of the ANK2/RABGAP1L complex which is required for the polarized recycling of fibronectin receptor ITGA5 ITGB1 to the plasma membrane that enables continuous directional cell migration (By similarity)","subcellular_location":"Cytoplasm, cytoskeleton; Membrane; Cytoplasm, myofibril, sarcomere, M line; Apical cell membrane; Cell membrane; Postsynaptic cell membrane; Early endosome; Recycling endosome; Lysosome; Mitochondrion; Cytoplasm, myofibril, sarcomere, Z line; Cell membrane, sarcolemma, T-tubule","url":"https://www.uniprot.org/uniprotkb/Q01484/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ANK2","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/ANK2","total_profiled":1310},"omim":[{"mim_id":"620262","title":"ANKYRIN REPEAT DOMAIN-CONTAINING PROTEIN 36; ANKRD36","url":"https://www.omim.org/entry/620262"},{"mim_id":"619475","title":"DEVELOPMENTAL DELAY, IMPAIRED SPEECH, AND BEHAVIORAL ABNORMALITIES; DDISBA","url":"https://www.omim.org/entry/619475"},{"mim_id":"614758","title":"DYNACTIN 4; DCTN4","url":"https://www.omim.org/entry/614758"},{"mim_id":"605427","title":"TRANSIENT RECEPTOR POTENTIAL CATION CHANNEL, SUBFAMILY V, MEMBER 4; TRPV4","url":"https://www.omim.org/entry/605427"},{"mim_id":"601581","title":"NEURONAL CELL ADHESION MOLECULE; NRCAM","url":"https://www.omim.org/entry/601581"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Acrosome","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"retina","ntpm":118.1},{"tissue":"skeletal muscle","ntpm":120.2}],"url":"https://www.proteinatlas.org/search/ANK2"},"hgnc":{"alias_symbol":["FAP87","CFAP87"],"prev_symbol":["LQT4"]},"alphafold":{"accession":"Q01484","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q01484","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q01484-7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q01484-7-F1-predicted_aligned_error_v6.png","plddt_mean":61.78},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ANK2","jax_strain_url":"https://www.jax.org/strain/search?query=ANK2"},"sequence":{"accession":"Q01484","fasta_url":"https://rest.uniprot.org/uniprotkb/Q01484.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q01484/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q01484"}},"corpus_meta":[{"pmid":"17242276","id":"PMC_17242276","title":"Defining the cellular phenotype of \"ankyrin-B syndrome\" variants: human ANK2 variants associated with clinical phenotypes display a spectrum of activities in cardiomyocytes.","date":"2007","source":"Circulation","url":"https://pubmed.ncbi.nlm.nih.gov/17242276","citation_count":128,"is_preprint":false},{"pmid":"31285321","id":"PMC_31285321","title":"ANK2 autism mutation targeting giant ankyrin-B promotes axon branching and ectopic connectivity.","date":"2019","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/31285321","citation_count":85,"is_preprint":false},{"pmid":"29328428","id":"PMC_29328428","title":"Regulation of drug resistance and metastasis of gastric cancer cells via the microRNA647-ANK2 axis.","date":"2018","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29328428","citation_count":46,"is_preprint":false},{"pmid":"38290518","id":"PMC_38290518","title":"Physical and functional convergence of the autism risk genes Scn2a and Ank2 in neocortical pyramidal cell dendrites.","date":"2024","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/38290518","citation_count":38,"is_preprint":false},{"pmid":"28196901","id":"PMC_28196901","title":"Novel Variant in the ANK2 Membrane-Binding Domain Is Associated With Ankyrin-B Syndrome and Structural Heart Disease in a First Nations Population With a High Rate of Long QT Syndrome.","date":"2017","source":"Circulation. Cardiovascular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28196901","citation_count":37,"is_preprint":false},{"pmid":"18790697","id":"PMC_18790697","title":"Exon organization and novel alternative splicing of the human ANK2 gene: implications for cardiac function and human cardiac disease.","date":"2008","source":"Journal of molecular and cellular cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/18790697","citation_count":33,"is_preprint":false},{"pmid":"32853419","id":"PMC_32853419","title":"lncRNA ZNF667-AS1 (NR_036521.1) inhibits the progression of colorectal cancer via regulating ANK2/JAK2 expression.","date":"2020","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/32853419","citation_count":27,"is_preprint":false},{"pmid":"20031550","id":"PMC_20031550","title":"Common genetic variants in ANK2 modulate QT interval: results from the KORA study.","date":"2008","source":"Circulation. 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Ankyrin-B-dependent protein interactions regulate cardiac electrogenesis.\",\n      \"method\": \"Primary cardiomyocyte assays with 9 nonsynonymous ANK2 variants; loss-of-function characterization\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean cellular loss-of-function assays with multiple variants, single lab, direct phenotypic readouts in cardiomyocytes\",\n      \"pmids\": [\"17242276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Giant ankyrin-B (the neurospecific alternatively spliced ANK2 isoform) localizes to periodic axonal plasma membrane domains through L1 cell-adhesion molecule and couples microtubules to the plasma membrane, thereby preventing microtubule entry into nascent axon branches and limiting axon branching.\",\n      \"method\": \"Mouse model of human ASD mutation; cultured neuron branching assays; live imaging; genetic loss-of-function; behavioral analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal functional interaction established with L1-CAM, multiple orthogonal methods (imaging, genetics, behavior), replicated across conditions\",\n      \"pmids\": [\"31285321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Ankyrin-B is essential for scaffolding NaV1.2 (encoded by SCN2A) to the dendritic membrane of neocortical pyramidal neurons; Ank2 haploinsufficiency phenocopies intrinsic dendritic excitability and synaptic deficits seen in Scn2a+/- neurons, establishing a direct convergent link between these two ASD risk genes.\",\n      \"method\": \"Mouse conditional knockout (Ank2 haploinsufficiency); electrophysiology; immunofluorescence localization of NaV1.2 in dendrites\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined cellular phenotype, direct localization experiment with functional consequence, phenocopy epistasis between two genes\",\n      \"pmids\": [\"38290518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ANK2 variant p.S646F (in the membrane-binding domain) causes reduced ankyrin-B expression in H9c2 cells and aberrant cardiomyocyte localization, and results in loss of normal membrane targeting of the Na/Ca exchanger (a known ankyrin-B binding partner), identifying the membrane-binding domain as critical for ankyrin-B function.\",\n      \"method\": \"Bacterial expression for folding assessment; H9c2 cell expression; primary cardiomyocyte localization assays; immunofluorescence of Na/Ca exchanger targeting\",\n      \"journal\": \"Circulation. Cardiovascular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional consequence, multiple cell-based methods, single lab\",\n      \"pmids\": [\"28196901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Ank2 knockout restricted to cortical and hippocampal excitatory neurons reduces total levels and density of Kv7.2/KCNQ2 and Kv7.3/KCNQ3 potassium channels at the axon initial segment (AIS) and causes elongated AIS, resulting in abnormally increased neuronal excitability and seizure-related death; Kv7 agonist retigabine rescues these phenotypes.\",\n      \"method\": \"Conditional knockout mice (Ank2-cKO); electrophysiology; immunofluorescence of AIS markers and Kv7 channels; pharmacological rescue with retigabine\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean conditional KO with defined cellular and in vivo phenotype, direct AIS localization data, pharmacological rescue, multiple orthogonal methods\",\n      \"pmids\": [\"37321992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ANK2 loss-of-function in hiPSC-derived neurons produces hyperactive and desynchronized neuronal network activity (measured by MEA), increased somatodendritic complexity, altered axon initial segment (AIS) structure, and impaired activity-dependent AIS plasticity.\",\n      \"method\": \"CRISPR/Cas9 heterozygous ANK2 LoF allele in hiPSCs; differentiation to excitatory neurons; micro-electrode array (MEA) electrophysiology; morphological characterization of AIS\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — CRISPR-engineered human neuronal model, MEA functional readout, AIS structural analysis, multiple orthogonal methods in single study\",\n      \"pmids\": [\"37195288\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Prenatal (but not adolescent) deletion of Ank2 in cortical excitatory neurons and oligodendrocytes causes spontaneous seizures, network hyperexcitability/hypersynchrony, and upregulation of dendritic spine plasticity-regulatory proteins and downregulation of intermediate filaments at synaptic membranes. Ankyrin-B interactome contains autism/epilepsy risk factors and synaptic proteins. AMPA receptor antagonist perampanel restores cortical activity.\",\n      \"method\": \"Conditional knockout mice (Ank2-/-:Emx1-Cre vs Ank2-/-:CaMKIIα-Cre); calcium imaging of cortical slices; quantitative proteomic analysis of synaptic membranes; interactome characterization; pharmacological rescue\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple conditional KO models, calcium imaging, quantitative proteomics of synaptic membranes, interactome, pharmacological rescue — multiple orthogonal methods\",\n      \"pmids\": [\"37428632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ANK2 variant p.L1622I displays reduced posttranslational expression in vivo, resulting in reduced cardiac ankyrin-B expression and reduced association with the Na/Ca exchanger binding partner; knock-in mice show arrhythmias, action potential duration increases, and afterdepolarizations.\",\n      \"method\": \"Knock-in mouse model; co-immunoprecipitation for Na/Ca exchanger association; in vivo electrophysiology; cellular action potential recordings\",\n      \"journal\": \"Heart rhythm\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knock-in animal model with defined in vivo and cellular phenotypes, Co-IP for binding partner, single lab\",\n      \"pmids\": [\"27298202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ANK2-E1813K diminishes currents mediated by combined wild-type and H562R KCNH2 subunits in Xenopus oocytes, indicating that ANK2 functionally interacts with KCNH2 (hERG) to modulate potassium channel current and QT interval duration.\",\n      \"method\": \"Voltage-clamp recordings in Xenopus oocytes with co-expression of ANK2 C-terminal regulatory domain and KCNH2 constructs; HEK293 trafficking assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro electrophysiology reconstitution in Xenopus oocytes, single lab, limited to C-terminal domain of ANK2\",\n      \"pmids\": [\"30929919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ANK2 (Ser3781) phosphorylation is dramatically reduced (>300-fold) in brains of PINK1-KO+A53T-SNCA mice, and ANK2/MAP1B expression depends on PINK1 levels, linking ANK2 post-translational phosphorylation to the PINK1/Parkin pathway.\",\n      \"method\": \"Quantitative label-free global phosphoproteomic mass spectrometry of mouse brain hemispheres; western blot validation of ANK2/MAP1B expression relative to PINK1 levels\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative phosphoproteomics plus western blot validation, in vivo mouse model, single lab\",\n      \"pmids\": [\"31277379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ANK2 translation occurs specifically after nuclear envelope breakdown in mouse oocytes, with Ank2.3 mRNA localizing to the forming spindle; prevention of ANK2 translation causes cytokinesis abnormalities in oocytes. The 5'UTR contains an oligo-pyrimidine motif determining cap-dependent translation.\",\n      \"method\": \"mRNA localization in oocytes; translation inhibition experiments; cytokinesis phenotype quantification; 5'UTR motif analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional consequence (cytokinesis defect upon translation inhibition), single lab, two methods\",\n      \"pmids\": [\"31511568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ANK2 regulates neural stem cell differentiation and neuronal migration in the embryonic cerebral cortex; Ank2 knockdown via in utero electroporation alters expression of genes involved in neural development.\",\n      \"method\": \"In utero electroporation knockdown in mouse embryonic cerebral cortex; immunofluorescence; gene expression analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct loss-of-function in vivo with cellular phenotype (migration, differentiation), single lab, single primary method\",\n      \"pmids\": [\"35313230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ANK2 deficiency induces mitochondrial cristae disorganization and membrane hyperpolarization, leading to bioenergetic stress and activation of the mitochondrial antiviral-signaling protein (MAVS); MAVS oligomerization enhances IL-6/IL-8 secretion, establishing an ANK2-MAVS-IL-8 axis connecting mitochondrial dysfunction to vascular inflammation.\",\n      \"method\": \"ANK2 knockdown cellular models; multi-omics (RNA-seq, proteomics, metabolomics, ATAC-seq); mitochondrial morphology and membrane potential assays; cytokine secretion measurement\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multi-omics plus functional assays in knockdown model, single lab, multiple orthogonal approaches\",\n      \"pmids\": [\"41248744\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP46 stabilizes ANK2 protein by deubiquitination (preventing its degradation), and elevated ANK2 in hypoxia/reoxygenation-treated cardiomyocytes promotes apoptosis, inflammation, and ferroptosis; USP46 knockdown reduces ANK2 and alleviates myocardial injury in rats.\",\n      \"method\": \"Cycloheximide chase assay; ubiquitination assay; siRNA knockdown; flow cytometry for apoptosis; in vivo rat I/R model\",\n      \"journal\": \"Journal of biochemical and molecular toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cycloheximide chase and ubiquitination assay directly demonstrate USP46-mediated deubiquitination of ANK2, single lab\",\n      \"pmids\": [\"40878243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AlphaFold modeling and mutagenesis identified a pocket in the ANK2 membrane-binding domain that engages NrCAM at the conserved FIGQY cytoplasmic motif, and key interactions between the ANK2 spectrin-binding domain and β2-Spectrin repeats 14-15. ASD missense mutation AnkB A368G (NrCAM binding pocket) disrupted NrCAM association and impaired Semaphorin 3F-induced spine pruning in cortical neurons; AnkB R977Q disrupted β2-Spectrin association.\",\n      \"method\": \"AlphaFold structural modeling; co-immunoprecipitation from HEK293 cells with mutant constructs; cortical neuron spine pruning assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — structure-guided mutagenesis validated by Co-IP and neuronal functional assay, preprint, single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Ankyrin-B and NrCAM mediate perisomatic synaptic contact between CCK basket interneurons and pyramidal neurons in mouse mPFC; deletion of Ankyrin-B from pyramidal neurons (via Nex1Cre-ERT2:Ank2flox/flox) decreases CCK-BC synaptic puncta on PN soma, while PV-BC contacts are unaffected.\",\n      \"method\": \"Conditional knockout (Nex1Cre-ERT2:Ank2flox/flox); immunolabeling for CCK-BC and PV-BC synaptic markers (VGLUT3, VGAT); CCK-BC reporter mouse (tdT at Sncg locus)\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean conditional KO with cell-type specific synaptic phenotype, multiple marker controls, preprint, single lab\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PTBP2 splicing regulator controls ANK2 exon 36 inclusion; loss of PTBP2 promotes near-complete inclusion of ANK2 exon 36, and this isoform switch is mechanistically required for RPE-to-neuron conversion — loss of exon 36 impairs neuronal induction, and re-expression of the exon-36-containing isoform restores conversion efficiency.\",\n      \"method\": \"PTBP2 knockdown in hRPE-19 cells; transcriptomic and splicing analysis; functional rescue assays with ANK2 exon 36 isoform\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional rescue assay establishes isoform-specific mechanism, single lab, transcriptomic validation\",\n      \"pmids\": [\"41555757\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Ankyrin-B (ANK2) is a multifunctional scaffolding protein that recruits and stabilizes ion channels (NaV1.2, Na/Ca exchanger, KCNH2, Kv7.2/3), transporters, and cell adhesion molecules (L1-CAM, NrCAM) to specialized membrane domains in cardiomyocytes and neurons via its membrane-binding and spectrin-binding domains; in the heart, loss of ankyrin-B disrupts Na/Ca exchanger targeting and causes arrhythmias, while in neurons the giant brain isoform couples microtubules to the axonal plasma membrane through L1-CAM to limit axon branching, scaffolds NaV1.2 to dendritic membranes, and maintains Kv7 channel density at the axon initial segment to control excitability — with USP46-mediated deubiquitination stabilizing ANK2 protein and PINK1-dependent phosphorylation at Ser3781 modulating its function.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"Ankyrin-B (ANK2) is a multifunctional membrane scaffolding protein that recruits and stabilizes ion channels, transporters, and cell adhesion molecules at specialized plasma membrane domains in both cardiomyocytes and neurons [#3, #2]. In the heart, ankyrin-B engages the Na/Ca exchanger through its membrane-binding domain, and loss-of-function variants that reduce ankyrin-B expression or membrane targeting disrupt Na/Ca exchanger localization and produce arrhythmias, action potential prolongation, and afterdepolarizations [#0, #3, #7]; it also functionally modulates the KCNH2 (hERG) potassium channel current [#8]. In the nervous system, the giant neurospecific isoform localizes to periodic axonal membrane domains via the L1 cell-adhesion molecule and couples microtubules to the plasma membrane, thereby restricting microtubule entry into nascent branches and limiting axon branching [#1]. Ankyrin-B scaffolds NaV1.2 (SCN2A) to dendritic membranes of neocortical pyramidal neurons, converging functionally with SCN2A as an autism risk gene [#2], and maintains Kv7.2/Kv7.3 (KCNQ2/KCNQ3) channel density and normal axon initial segment structure, with its loss causing AIS elongation, network hyperexcitability, and seizure-related death that is rescued by the Kv7 agonist retigabine [#4, #5, #6]. Through NrCAM binding at a defined membrane-binding-domain pocket and β2-spectrin engagement via its spectrin-binding domain, ankyrin-B mediates Semaphorin 3F–dependent spine pruning and perisomatic CCK basket interneuron synaptic contacts onto pyramidal neurons [#14, #15]. ANK2 also functions in cortical neural stem cell differentiation and neuronal migration [#11] and in oocyte cytokinesis, where its spindle-localized isoform is translated after nuclear envelope breakdown [#10]. ANK2 protein levels are controlled post-translationally by USP46-mediated deubiquitination [#13] and by PINK1-dependent Ser3781 phosphorylation [#9], and isoform identity is governed by PTBP2-regulated exon 36 splicing [#16].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established that ANK2 variants causing graded cellular loss-of-function map onto clinical arrhythmia severity, framing ankyrin-B as a dose-sensitive regulator of cardiac electrogenesis.\",\n      \"evidence\": \"Primary cardiomyocyte assays of 9 nonsynonymous ANK2 variants\",\n      \"pmids\": [\"17242276\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not resolve which molecular interactions each variant disrupts\", \"Mechanism linking expression level to electrical phenotype not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Localized ankyrin-B function to its membrane-binding domain by showing a domain variant reduces expression and abolishes Na/Ca exchanger membrane targeting.\",\n      \"evidence\": \"H9c2 and primary cardiomyocyte expression/localization assays with p.S646F\",\n      \"pmids\": [\"28196901\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, cell-based only\", \"Did not test in vivo cardiac consequences of this variant\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated the giant neuronal isoform couples microtubules to the axonal membrane via L1-CAM to limit axon branching, defining a neuronal cytoskeleton-membrane scaffolding role distinct from cardiac function.\",\n      \"evidence\": \"Mouse ASD-mutation model, neuron branching assays, live imaging, behavior\",\n      \"pmids\": [\"31285321\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address dendritic or AIS roles\", \"Branching mechanism in vivo circuit consequences incomplete\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Confirmed in vivo that a destabilizing variant lowers cardiac ankyrin-B and Na/Ca exchanger association, causing arrhythmia and afterdepolarizations, linking protein stability to electrical phenotype.\",\n      \"evidence\": \"p.L1622I knock-in mouse, Co-IP, in vivo and cellular electrophysiology\",\n      \"pmids\": [\"27298202\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Mechanism of reduced posttranslational stability not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended ankyrin-B channel partnerships by showing functional interaction with KCNH2 (hERG) affecting potassium current and QT duration.\",\n      \"evidence\": \"Voltage-clamp in Xenopus oocytes with ANK2 C-terminal domain; HEK293 trafficking\",\n      \"pmids\": [\"30929919\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Limited to C-terminal domain reconstitution\", \"No native cardiomyocyte validation\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected ANK2 to a neurodegeneration pathway by identifying PINK1-dependent Ser3781 phosphorylation and PINK1-dependent ANK2 expression.\",\n      \"evidence\": \"Quantitative brain phosphoproteomics and western blot in PINK1-KO+A53T-SNCA mice\",\n      \"pmids\": [\"31277379\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of Ser3781 phosphorylation unknown\", \"Direct vs indirect link to PINK1 not resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealed a non-neuronal, non-cardiac role: spindle-localized ANK2 translation after nuclear envelope breakdown is required for oocyte cytokinesis.\",\n      \"evidence\": \"Oocyte mRNA localization, translation inhibition, cytokinesis phenotype, 5'UTR motif analysis\",\n      \"pmids\": [\"31511568\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular partners at the spindle not identified\", \"Mechanism of cytokinesis defect undefined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Implicated ANK2 in early cortical development through control of neural stem cell differentiation and neuronal migration.\",\n      \"evidence\": \"In utero electroporation knockdown, immunofluorescence, gene expression analysis\",\n      \"pmids\": [\"35313230\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single primary method\", \"Direct molecular effectors of migration not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined ankyrin-B as a maintainer of Kv7.2/Kv7.3 density and AIS structure, with loss causing hyperexcitability and seizure death rescuable by a Kv7 agonist.\",\n      \"evidence\": \"Conditional Ank2-cKO mice, electrophysiology, AIS immunofluorescence, retigabine rescue\",\n      \"pmids\": [\"37321992\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct ankyrin-B/Kv7 binding interface not mapped\", \"Whether AIS elongation is cause or consequence unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Validated ANK2 LoF phenotypes in a human neuronal model, showing network hyperactivity, altered AIS structure, and impaired activity-dependent AIS plasticity.\",\n      \"evidence\": \"CRISPR heterozygous LoF hiPSC-derived neurons, MEA, AIS morphology\",\n      \"pmids\": [\"37195288\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular driver of impaired AIS plasticity not identified\", \"Channel-level mechanism in human neurons not dissected\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed developmental-timing dependence of ANK2 loss and identified a synaptic interactome plus pharmacological rescue, linking ankyrin-B to network hypersynchrony.\",\n      \"evidence\": \"Multiple conditional KO mice, calcium imaging, synaptic membrane proteomics, perampanel rescue\",\n      \"pmids\": [\"37428632\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect membership of interactome partners not all validated\", \"Mechanism of intermediate filament downregulation unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established convergence of two ASD risk genes by showing ankyrin-B scaffolds NaV1.2 to dendritic membranes and Ank2 haploinsufficiency phenocopies Scn2a loss.\",\n      \"evidence\": \"Conditional KO mice, dendritic electrophysiology, NaV1.2 immunolocalization\",\n      \"pmids\": [\"38290518\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct ankyrin-B/NaV1.2 binding interface not defined here\", \"Whether convergence extends to synaptic deficits mechanistically incomplete\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified a cell-type-specific synaptic role: ankyrin-B and NrCAM mediate CCK basket interneuron perisomatic contacts onto pyramidal neurons.\",\n      \"evidence\": \"Conditional KO, CCK-BC/PV-BC synaptic marker immunolabeling, reporter mouse (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, single lab\", \"Direct molecular requirement of NrCAM binding not separated from ankyrin-B loss\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Mapped the structural basis for ankyrin-B partner binding, defining an NrCAM-engaging pocket and β2-spectrin interface and linking an ASD mutation to disrupted Sema3F-dependent spine pruning.\",\n      \"evidence\": \"AlphaFold modeling, mutagenesis Co-IP from HEK293, cortical neuron spine pruning assay (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, single lab\", \"Structural model not experimentally validated by direct structure\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined post-translational control of ankyrin-B abundance via USP46 deubiquitination and linked elevated ANK2 to cardiomyocyte injury.\",\n      \"evidence\": \"Cycloheximide chase, ubiquitination assay, siRNA knockdown, rat I/R model\",\n      \"pmids\": [\"40878243\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct vs indirect USP46-ANK2 enzyme-substrate relationship in vivo not fully resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected ankyrin-B deficiency to mitochondrial dysfunction and MAVS-driven vascular inflammation, expanding its role beyond membrane scaffolding.\",\n      \"evidence\": \"ANK2 knockdown, multi-omics, mitochondrial morphology/potential assays, cytokine measurement\",\n      \"pmids\": [\"41248744\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking ankyrin-B to mitochondrial cristae unknown\", \"Whether effect is direct or secondary not established\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showed PTBP2-controlled ANK2 exon 36 splicing dictates an isoform required for RPE-to-neuron conversion, establishing isoform-specific functional identity.\",\n      \"evidence\": \"PTBP2 knockdown, splicing/transcriptomics, exon 36 isoform rescue in hRPE-19 cells\",\n      \"pmids\": [\"41555757\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional protein-level difference of exon 36 isoform not biochemically defined\", \"Relevance to in vivo neurogenesis unaddressed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How distinct ankyrin-B isoforms, their domain-specific partner repertoires, and post-translational regulators are coordinated to produce tissue-specific outcomes across heart, brain, mitochondria, and dividing cells remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified map linking isoform/domain to partner selection across tissues\", \"Functional roles of identified phosphorylation/ubiquitination sites not causally tested\", \"Mitochondrial and cell-division roles lack defined molecular mechanism\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 2, 3, 14]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [1, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 2, 3]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0112316\", \"supporting_discovery_ids\": []}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"L1CAM\",\n      \"SCN2A\",\n      \"SLC8A1\",\n      \"KCNH2\",\n      \"KCNQ2\",\n      \"KCNQ3\",\n      \"NRCAM\",\n      \"SPTBN1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}