{"gene":"ANKRD26","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":2014,"finding":"THC2-associated mutations in the 5' UTR of ANKRD26 disrupt binding of transcription factors RUNX1 and FLI1, preventing ANKRD26 silencing during late megakaryopoiesis. Persistent ANKRD26 expression increases signaling via the TPO/MPL pathway and impairs proplatelet formation; ERK inhibition rescues proplatelet formation in vitro.","method":"Patient-derived megakaryocytes, reporter assays, RUNX1/FLI1 ChIP/binding assays, ERK inhibitor rescue experiments","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods in primary patient cells with functional rescue; independently supported by later studies","pmids":["24430186"],"is_preprint":false},{"year":2020,"finding":"ANKRD26 localizes to centriolar distal appendages and recruits PIDD1 to this location; this interaction is required for PIDDosome activation (Caspase-2 cleavage of MDM2) following centrosome amplification, linking extra centrosomes to p53 stabilization and cell cycle arrest.","method":"Genome-wide screen, Co-IP, immunofluorescence localization, Caspase-2 activity assays, PIDD1 autoproteolysis assays, genetic knockouts","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — replicated independently by two labs in the same journal issue with reciprocal Co-IP, localization, and functional readouts","pmids":["33350486","33350495"],"is_preprint":false},{"year":2020,"finding":"TALPID3 and ANKRD26 form a complex with FBF1 at transition fibers (distal appendages) to regulate cilia gating; co-depletion of TALPID3 and ANKRD26 specifically impairs FBF1 recruitment to transition fibers in both C. elegans and mammalian cells.","method":"Forward genetic screen in C. elegans, Co-IP, immunofluorescence, genetic epistasis (double depletion), mammalian cell validation","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — ortholog function confirmed in mammalian cells, multiple orthogonal methods including genetic epistasis and reciprocal Co-IP","pmids":["32366837"],"is_preprint":false},{"year":2023,"finding":"ANKRD26 interacts with and modulates the activity of three homodimeric type I cytokine receptors (MPL, EPOR, G-CSFR); elevated ANKRD26 prevents receptor internalization, leading to increased downstream signaling and cytokine hypersensitivity in erythroid, megakaryocyte, and granulocyte progenitors.","method":"Co-IP in cell lines and primary patient cells, patient-derived iPSC models, receptor internalization assays, cytokine sensitivity assays","journal":"Haematologica","confidence":"High","confidence_rationale":"Tier 2 — multiple human-relevant in vitro models, Co-IP, and functional receptor internalization assays","pmids":["36794499"],"is_preprint":false},{"year":2007,"finding":"Partial inactivation of Ankrd26 in mice causes extreme obesity, insulin resistance, hyperphagia, and gigantism; the protein is expressed in hypothalamic arcuate and ventromedial nuclei, and loss leads to elevated phospho-Akt and mTOR in enlarged hearts.","method":"Mutant mouse model (partial gene inactivation), metabolic phenotyping, immunohistochemistry, western blot for phospho-Akt/mTOR","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — in vivo loss-of-function with multiple phenotypic readouts and biochemical pathway analysis","pmids":["18162531"],"is_preprint":false},{"year":2011,"finding":"Ankrd26 disruption in mouse embryonic fibroblasts enhances adipogenesis via constitutive ERK activation; MEK inhibition blocks ERK activation and reduces adipogenesis induction, placing ANKRD26 upstream of ERK in the adipogenic pathway.","method":"Ankrd26-/- MEF adipogenesis assays, gene expression analysis, MEK inhibitor rescue experiments, western blot for phospho-ERK","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function with defined phenotype, pharmacological rescue, and pathway placement","pmids":["21669876"],"is_preprint":false},{"year":2012,"finding":"ANKRD26 interacts with TRIO, GPS2, DIPA, and HMMR (identified by yeast two-hybrid and co-immunoprecipitation); the C-terminus of ANKRD26 causes nuclear GPS2 and DIPA to translocate to the cytoplasm; knockdown of each partner increases adipogenesis in 3T3-L1 cells.","method":"Yeast two-hybrid, co-immunoprecipitation, subcellular localization by microscopy, siRNA knockdown with adipogenesis readout","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP/Y2H with functional follow-up in single study","pmids":["22666460"],"is_preprint":false},{"year":2014,"finding":"Disruption of Ankrd26 causes defects in primary cilia in CNS regions controlling appetite and energy homeostasis, representing a novel ciliopathy mechanism underlying hyperphagia and obesity in Ankrd26 knockout mice.","method":"Ankrd26-/- mouse model, histological and electron microscopic analysis of primary cilia in CNS","journal":"Brain structure & function","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo loss-of-function with direct morphological assessment of cilia, single study","pmids":["24633808"],"is_preprint":false},{"year":2011,"finding":"5' UTR mutations in ANKRD26 likely enhance ANKRD26 expression rather than cause haploinsufficiency, as demonstrated by luciferase reporter assay showing increased promoter activity with THC2-associated mutations.","method":"Luciferase reporter assay with 5' UTR constructs carrying THC2 mutations","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 3 — reporter assay in single study, consistent with later functional data","pmids":["21211618"],"is_preprint":false},{"year":2017,"finding":"N-terminal truncating ANKRD26 coding mutations (c.3G>A and c.105C>G) produce stable isoforms with strong ability to activate MAPK/ERK signaling, and are associated with ANKRD26 overexpression in AML patients.","method":"Patient cell functional studies, western blot, ERK signaling assays","journal":"Journal of hematology & oncology","confidence":"Medium","confidence_rationale":"Tier 3 — single study, cell-based functional assays with patient samples","pmids":["28100250"],"is_preprint":false},{"year":2024,"finding":"ANKRD26 uses an N-terminal amphipathic structure for plasma membrane binding and bending, self-associates to form clusters at the plasma membrane in response to retinoic acid, and is required for retinoic acid/BDNF-induced neuroblastoma differentiation; an AML-associated N-terminal truncating mutation abolishes membrane association and impairs differentiation.","method":"Subcellular localization by live imaging, gain-of-function and loss-of-function/rescue experiments, structural domain mutagenesis","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 — multiple methods including mutagenesis and rescue experiments, single study","pmids":["38493476"],"is_preprint":false},{"year":2021,"finding":"A large complex structural variant (paired-duplication inversion) creates a pathogenic gain-of-function WAC-ANKRD26 fusion transcript that causes inherited thrombocytopenia resembling THC2, demonstrating that persistent ANKRD26 expression (via fusion) during hematopoietic differentiation is the pathogenic mechanism.","method":"Long-read whole-genome sequencing, functional studies of fusion transcript expression and effect on ANKRD26 silencing","journal":"The Journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 — long-read sequencing plus functional validation, single study","pmids":["33857290"],"is_preprint":false},{"year":2024,"finding":"ANKRD26 interacts with ETV6 and retains it in the cytoplasm; GPS2 (a component of the NCoR complex) binds both ANKRD26 and ETV6, mediating their interaction; ANKRD26 overexpression deregulates ETV6 transcriptional repression, revealing an ANKRD26-ETV6-GPS2 axis.","method":"Co-IP, subcellular localization studies, transcriptional reporter assays","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP and localization with functional transcriptional readout, single study","pmids":["39791724"],"is_preprint":false},{"year":2024,"finding":"A novel 5' UTR variant (c.-107C>T) in the FLI1 binding site (not the RUNX1 site) of ANKRD26 disrupts FLI1 binding, sustains ANKRD26 expression in differentiating megakaryocytes, and impairs proplatelet formation, extending the functional regulatory region of ANKRD26.","method":"PBMCs differentiation assays, reporter assay, platelet ANKRD26 expression by qPCR, megakaryocyte functional studies","journal":"Clinical genetics","confidence":"Medium","confidence_rationale":"Tier 3 — multiple methods but single study, mechanistically confirmatory of established RUNX1/FLI1 regulatory mechanism","pmids":["38757516"],"is_preprint":false},{"year":2025,"finding":"Elevated ANKRD26 induces apoptosis in polyploid megakaryocytes via JUNB-mediated transcriptional activation of CDKN1A (p21), operating independently of the canonical p53-PIDDosome axis; ANKRD26 protein localizes to the centrosome in megakaryocytes.","method":"Single-cell transcriptomics of patient bone marrow, confocal imaging for centrosome localization, mechanistic pathway analysis in primary megakaryocytes","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 — multipatient single-cell analysis with orthogonal imaging, single study","pmids":["41538704"],"is_preprint":false},{"year":2024,"finding":"PIDDosome activation requires ANKRD26 to target PIDD1 to mother centrioles in cardiomyocytes during postnatal heart development; this limits CM polyploidization in a p53-independent but p21/Cdkn1a-dependent manner.","method":"Genetic deletion of PIDDosome components, nuclear RNA sequencing, DNA content analyses, postnatal developmental time course experiments in mice","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo genetic experiments with multiple readouts, but preprint","pmids":[],"is_preprint":true}],"current_model":"ANKRD26 is a plasma membrane- and centrosome-associated ankyrin repeat protein that (1) is transcriptionally silenced in late megakaryopoiesis by RUNX1/FLI1 binding to its 5' UTR, and 5' UTR mutations that prevent this silencing cause persistent ANKRD26 expression, which hyperactivates MAPK/ERK signaling and prevents proplatelet formation via sustained TPO/MPL, EPOR, and G-CSFR signaling by blocking receptor internalization; (2) localizes to centriolar distal appendages where it recruits PIDD1 to activate the PIDDosome (Caspase-2/MDM2/p53 axis) as a safeguard against centrosome amplification; (3) coordinates with TALPID3 to recruit FBF1 to transition fibers for cilia gating; (4) regulates adipogenesis and appetite via hypothalamic expression and ERK-dependent signaling; and (5) interacts with partners including TRIO, GPS2, HMMR, DIPA, and ETV6, with GPS2 mediating an ANKRD26-ETV6 cytoplasmic retention axis relevant to thrombocytopenia predisposition to leukemia."},"narrative":{"teleology":[{"year":2007,"claim":"The first in vivo loss-of-function study established that ANKRD26 is required for metabolic homeostasis, as partial inactivation caused extreme obesity, hyperphagia, and insulin resistance linked to elevated Akt/mTOR signaling in mice.","evidence":"Mutant mouse model with metabolic phenotyping, hypothalamic immunohistochemistry, and western blot","pmids":["18162531"],"confidence":"High","gaps":["Mechanism by which hypothalamic ANKRD26 controls appetite not defined","Direct molecular target in arcuate/ventromedial nuclei unknown"]},{"year":2011,"claim":"ANKRD26 was placed upstream of MAPK/ERK in adipogenesis: Ankrd26 disruption constitutively activated ERK and enhanced adipocyte differentiation, while separate reporter assays showed that THC2-associated 5′ UTR mutations increase rather than decrease ANKRD26 expression.","evidence":"Ankrd26−/− MEF adipogenesis assays with MEK inhibitor rescue; luciferase reporter assays with THC2 5′ UTR constructs","pmids":["21669876","21211618"],"confidence":"High","gaps":["Mechanism connecting ANKRD26 to ERK activation (direct or indirect) not resolved","Reporter assays did not identify the specific trans-acting factors"]},{"year":2012,"claim":"Identification of direct protein partners (TRIO, GPS2, DIPA, HMMR) revealed that ANKRD26 sequesters nuclear factors to the cytoplasm and that each partner functionally opposes adipogenesis.","evidence":"Yeast two-hybrid, Co-IP, subcellular localization, siRNA knockdown in 3T3-L1 cells","pmids":["22666460"],"confidence":"Medium","gaps":["Y2H interactions lack reciprocal validation in some cases","Stoichiometry and whether these form a single complex or separate binary interactions unknown","Relevance beyond adipogenesis not tested"]},{"year":2014,"claim":"The disease mechanism for THC2 was resolved: 5′ UTR mutations disrupt RUNX1/FLI1 binding, preventing transcriptional silencing of ANKRD26 during late megakaryopoiesis; persistent expression hyperactivates TPO/MPL–ERK signaling and blocks proplatelet formation, with ERK inhibition rescuing the defect.","evidence":"Patient-derived megakaryocytes, ChIP/binding assays for RUNX1/FLI1, ERK inhibitor rescue","pmids":["24430186"],"confidence":"High","gaps":["Whether ANKRD26 directly binds MPL or acts via an adaptor not determined","Mechanism of leukemia predisposition not explained by ERK hyperactivation alone"]},{"year":2014,"claim":"The obesity phenotype was connected to ciliogenesis: Ankrd26 knockout mice showed defective primary cilia in CNS appetite-regulating centers, establishing a ciliopathy mechanism for the metabolic phenotype.","evidence":"Histological and electron microscopic analysis of cilia in Ankrd26−/− mouse CNS","pmids":["24633808"],"confidence":"Medium","gaps":["Molecular role of ANKRD26 in cilia assembly versus maintenance not distinguished","Whether ciliary defects are cell-autonomous not tested"]},{"year":2020,"claim":"Two independent studies established ANKRD26 as a centriolar distal appendage protein that recruits PIDD1 to activate the PIDDosome checkpoint against centrosome amplification, and a parallel study showed ANKRD26 cooperates with TALPID3 to recruit FBF1 to transition fibers for cilia gating.","evidence":"Genome-wide screens, Co-IP, immunofluorescence, Caspase-2 activity assays, genetic epistasis in C. elegans and mammalian cells","pmids":["33350486","33350495","32366837"],"confidence":"High","gaps":["How ANKRD26 is itself recruited to distal appendages not known","Whether cilia gating and PIDDosome functions are coordinated or independent unclear","Structural basis of ANKRD26–PIDD1 interaction not resolved"]},{"year":2023,"claim":"The receptor-level mechanism was clarified: elevated ANKRD26 directly interacts with and prevents internalization of MPL, EPOR, and G-CSFR, explaining cytokine hypersensitivity across multiple hematopoietic lineages in THC2.","evidence":"Co-IP in cell lines and patient iPSC-derived cells, receptor internalization and cytokine sensitivity assays","pmids":["36794499"],"confidence":"High","gaps":["Binding interface on the receptors not mapped","Whether ANKRD26 blocks ubiquitin-dependent or clathrin-dependent internalization specifically is unknown"]},{"year":2024,"claim":"ANKRD26 was shown to bind and bend membranes via an N-terminal amphipathic structure, self-assemble into plasma membrane clusters in response to retinoic acid, and be required for neuroblastoma differentiation — with an AML-linked truncation abolishing membrane association.","evidence":"Live imaging, domain mutagenesis, gain/loss-of-function and rescue experiments in neuroblastoma cells","pmids":["38493476"],"confidence":"Medium","gaps":["Lipid specificity of membrane binding not characterized","Relevance of membrane remodeling to megakaryocyte biology not tested"]},{"year":2024,"claim":"An ANKRD26–GPS2–ETV6 cytoplasmic retention axis was identified, explaining how ANKRD26 overexpression deregulates the tumor suppressor ETV6, providing a mechanistic link between THC2 and leukemia predisposition.","evidence":"Co-IP, subcellular localization, transcriptional reporter assays","pmids":["39791724"],"confidence":"Medium","gaps":["Single study without independent replication","In vivo relevance to leukemogenesis not demonstrated","Whether GPS2 bridges or stabilizes the ANKRD26–ETV6 interaction directly is unclear"]},{"year":2025,"claim":"In polyploid megakaryocytes, elevated ANKRD26 drives apoptosis through JUNB-mediated CDKN1A (p21) induction independently of the canonical p53–PIDDosome pathway, revealing a p53-independent arm of ANKRD26 centrosomal signaling.","evidence":"Single-cell transcriptomics of patient bone marrow, confocal centrosome imaging in megakaryocytes","pmids":["41538704"],"confidence":"Medium","gaps":["Mechanism linking centrosomal ANKRD26 to JUNB activation not defined","Single study requiring independent confirmation","Relationship to PIDDosome-dependent p21 induction in cardiomyocytes unclear"]},{"year":null,"claim":"Key unresolved questions include: how ANKRD26 is recruited to distal appendages, whether its membrane-remodeling and centrosome functions are coordinated, the structural basis of receptor interaction and internalization blockade, and the mechanistic pathway from ANKRD26 overexpression to myeloid transformation.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of ANKRD26 or its complexes exists","Direct in vivo demonstration of leukemia initiation by ANKRD26 overexpression is lacking","Relative contribution of PIDDosome-dependent versus JUNB/p21-dependent pathways in megakaryocytes not delineated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,3,5]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,6,12]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[10]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,10]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[1,14]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[2,7]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,3,5,9]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[2,7]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,10]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,9,11]}],"complexes":["PIDDosome"],"partners":["PIDD1","GPS2","TRIO","HMMR","ETV6","FBF1","TALPID3"],"other_free_text":[]},"mechanistic_narrative":"ANKRD26 is an ankyrin repeat protein that functions at centrosomes and the plasma membrane to integrate cytokine receptor signaling, centrosome surveillance, and ciliogenesis. During megakaryopoiesis, ANKRD26 is normally silenced by RUNX1/FLI1 binding to its 5′ UTR; gain-of-function mutations that prevent this silencing cause persistent ANKRD26 expression, which blocks internalization of type I cytokine receptors (MPL, EPOR, G-CSFR), hyperactivates MAPK/ERK signaling, and impairs proplatelet formation, causing thrombocytopenia 2 (THC2) with predisposition to myeloid malignancies [PMID:24430186, PMID:36794499, PMID:33857290]. At centriolar distal appendages, ANKRD26 recruits PIDD1 to activate the PIDDosome–Caspase-2–MDM2–p53 axis as a checkpoint against centrosome amplification, and cooperates with TALPID3 to recruit FBF1 for cilia gating [PMID:33350486, PMID:32366837]. ANKRD26 also uses an N-terminal amphipathic structure for plasma membrane binding and self-assembly, and its loss in mice causes obesity, hyperphagia, enhanced adipogenesis via constitutive ERK activation, and CNS ciliary defects [PMID:38493476, PMID:18162531, PMID:21669876, PMID:24633808]."},"prefetch_data":{"uniprot":{"accession":"Q9UPS8","full_name":"Ankyrin repeat domain-containing protein 26","aliases":[],"length_aa":1710,"mass_kda":196.4,"function":"Acts as a regulator of adipogenesis. Involved in the regulation of the feeding behavior","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q9UPS8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ANKRD26","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":[{"gene":"ARID1A","stoichiometry":0.2},{"gene":"GOLT1B","stoichiometry":0.2},{"gene":"MIF","stoichiometry":0.2},{"gene":"RAB9A","stoichiometry":0.2},{"gene":"SLC2A8","stoichiometry":0.2},{"gene":"VPS35","stoichiometry":0.2},{"gene":"WASF2","stoichiometry":0.2},{"gene":"WDR3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ANKRD26","total_profiled":1310},"omim":[{"mim_id":"616618","title":"ACYL-CoA-BINDING DOMAIN-CONTAINING PROTEIN 5; ACBD5","url":"https://www.omim.org/entry/616618"},{"mim_id":"611399","title":"SODIUM CHANNEL AND CLATHRIN LINKER 1; SCLT1","url":"https://www.omim.org/entry/611399"},{"mim_id":"610855","title":"ANKYRIN REPEAT DOMAIN-CONTAINING PROTEIN 26; ANKRD26","url":"https://www.omim.org/entry/610855"},{"mim_id":"608221","title":"MICROTUBULE-ASSOCIATED SERINE/THREONINE KINASE-LIKE; MASTL","url":"https://www.omim.org/entry/608221"},{"mim_id":"601665","title":"OBESITY","url":"https://www.omim.org/entry/601665"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Vesicles","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ANKRD26"},"hgnc":{"alias_symbol":["KIAA1074"],"prev_symbol":["THC2"]},"alphafold":{"accession":"Q9UPS8","domains":[{"cath_id":"1.25.40.20","chopping":"50-217","consensus_level":"medium","plddt":86.5808,"start":50,"end":217},{"cath_id":"1.20.5","chopping":"723-879","consensus_level":"medium","plddt":83.3686,"start":723,"end":879}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UPS8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UPS8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UPS8-F1-predicted_aligned_error_v6.png","plddt_mean":62.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ANKRD26","jax_strain_url":"https://www.jax.org/strain/search?query=ANKRD26"},"sequence":{"accession":"Q9UPS8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UPS8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UPS8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UPS8"}},"corpus_meta":[{"pmid":"21467542","id":"PMC_21467542","title":"Mutations in ANKRD26 are responsible for a frequent form of inherited thrombocytopenia: analysis of 78 patients from 21 families.","date":"2011","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/21467542","citation_count":224,"is_preprint":false},{"pmid":"21211618","id":"PMC_21211618","title":"Mutations in the 5' UTR of ANKRD26, the ankirin repeat domain 26 gene, cause an autosomal-dominant form of inherited thrombocytopenia, THC2.","date":"2011","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21211618","citation_count":174,"is_preprint":false},{"pmid":"24430186","id":"PMC_24430186","title":"Thrombocytopenia-associated mutations in the ANKRD26 regulatory region induce MAPK hyperactivation.","date":"2014","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/24430186","citation_count":141,"is_preprint":false},{"pmid":"18162531","id":"PMC_18162531","title":"A model for obesity and gigantism due to disruption of the Ankrd26 gene.","date":"2007","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/18162531","citation_count":60,"is_preprint":false},{"pmid":"33350486","id":"PMC_33350486","title":"Centriolar distal appendages activate the centrosome-PIDDosome-p53 signalling axis via ANKRD26.","date":"2020","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/33350486","citation_count":59,"is_preprint":false},{"pmid":"33350495","id":"PMC_33350495","title":"ANKRD26 recruits PIDD1 to centriolar distal appendages to activate the PIDDosome following centrosome amplification.","date":"2020","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/33350495","citation_count":59,"is_preprint":false},{"pmid":"23223974","id":"PMC_23223974","title":"Ubiquitin/proteasome-rich particulate cytoplasmic structures (PaCSs) in the platelets and megakaryocytes of ANKRD26-related thrombo-cytopenia.","date":"2012","source":"Thrombosis and haemostasis","url":"https://pubmed.ncbi.nlm.nih.gov/23223974","citation_count":49,"is_preprint":false},{"pmid":"21669876","id":"PMC_21669876","title":"Ankrd26 gene disruption enhances adipogenesis of mouse embryonic fibroblasts.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21669876","citation_count":46,"is_preprint":false},{"pmid":"28100250","id":"PMC_28100250","title":"5'UTR point substitutions and N-terminal truncating mutations of ANKRD26 in acute myeloid leukemia.","date":"2017","source":"Journal of hematology & oncology","url":"https://pubmed.ncbi.nlm.nih.gov/28100250","citation_count":37,"is_preprint":false},{"pmid":"28266632","id":"PMC_28266632","title":"Specific CpG hyper-methylation leads to Ankrd26 gene down-regulation in white adipose tissue of a mouse model of diet-induced obesity.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28266632","citation_count":37,"is_preprint":false},{"pmid":"22666460","id":"PMC_22666460","title":"ANKRD26 and its interacting partners TRIO, GPS2, HMMR and DIPA regulate adipogenesis in 3T3-L1 cells.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22666460","citation_count":30,"is_preprint":false},{"pmid":"24633808","id":"PMC_24633808","title":"A novel form of ciliopathy underlies hyperphagia and obesity in Ankrd26 knockout mice.","date":"2014","source":"Brain structure & function","url":"https://pubmed.ncbi.nlm.nih.gov/24633808","citation_count":30,"is_preprint":false},{"pmid":"28976612","id":"PMC_28976612","title":"Inherited thrombocytopenia caused by ANKRD26 mutations misdiagnosed and treated as myelodysplastic syndrome: report on two cases.","date":"2017","source":"Journal of thrombosis and haemostasis : JTH","url":"https://pubmed.ncbi.nlm.nih.gov/28976612","citation_count":28,"is_preprint":false},{"pmid":"20842219","id":"PMC_20842219","title":"Tumor Suppressor RARRES1 Regulates DLG2, PP2A, VCP, EB1, and Ankrd26.","date":"2010","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/20842219","citation_count":26,"is_preprint":false},{"pmid":"35244185","id":"PMC_35244185","title":"Exosome‑derived lncRNA‑Ankrd26 promotes dental pulp restoration by regulating miR‑150‑TLR4 signaling.","date":"2022","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/35244185","citation_count":25,"is_preprint":false},{"pmid":"32366837","id":"PMC_32366837","title":"TALPID3 and ANKRD26 selectively orchestrate FBF1 localization and cilia gating.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/32366837","citation_count":23,"is_preprint":false},{"pmid":"33857290","id":"PMC_33857290","title":"Familial thrombocytopenia due to a complex structural variant resulting in a WAC-ANKRD26 fusion transcript.","date":"2021","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33857290","citation_count":22,"is_preprint":false},{"pmid":"35587581","id":"PMC_35587581","title":"Prevalence and natural history of variants in the ANKRD26 gene: a short review and update of reported cases.","date":"2022","source":"Platelets","url":"https://pubmed.ncbi.nlm.nih.gov/35587581","citation_count":21,"is_preprint":false},{"pmid":"21842266","id":"PMC_21842266","title":"Partial inactivation of Ankrd26 causes diabetes with enhanced insulin responsiveness of adipose tissue in mice.","date":"2011","source":"Diabetologia","url":"https://pubmed.ncbi.nlm.nih.gov/21842266","citation_count":19,"is_preprint":false},{"pmid":"35751752","id":"PMC_35751752","title":"ANKRD26-Related Thrombocytopenia and Predisposition to Myeloid Neoplasms.","date":"2022","source":"Current hematologic malignancy reports","url":"https://pubmed.ncbi.nlm.nih.gov/35751752","citation_count":18,"is_preprint":false},{"pmid":"27123948","id":"PMC_27123948","title":"Clinical and laboratory characteristics in congenital ANKRD26 mutation-associated thrombocytopenia: A detailed phenotypic study of a family.","date":"2016","source":"Platelets","url":"https://pubmed.ncbi.nlm.nih.gov/27123948","citation_count":18,"is_preprint":false},{"pmid":"31801613","id":"PMC_31801613","title":"Epigenetic silencing of the ANKRD26 gene correlates to the pro-inflammatory profile and increased cardio-metabolic risk factors in human obesity.","date":"2019","source":"Clinical epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/31801613","citation_count":16,"is_preprint":false},{"pmid":"29185836","id":"PMC_29185836","title":"Exome-chip meta-analysis identifies association between variation in ANKRD26 and platelet aggregation.","date":"2017","source":"Platelets","url":"https://pubmed.ncbi.nlm.nih.gov/29185836","citation_count":15,"is_preprint":false},{"pmid":"31425920","id":"PMC_31425920","title":"ANKRD26-RET - A novel gene fusion involving RET in papillary thyroid carcinoma.","date":"2019","source":"Cancer genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31425920","citation_count":15,"is_preprint":false},{"pmid":"30147876","id":"PMC_30147876","title":"An ANKRD26 nonsense somatic mutation in a female with epidermodysplasia verruciformis (Tree Man Syndrome).","date":"2018","source":"Clinical case reports","url":"https://pubmed.ncbi.nlm.nih.gov/30147876","citation_count":15,"is_preprint":false},{"pmid":"22102272","id":"PMC_22102272","title":"Thrombocytopenias due to gray platelet syndrome or THC2 mutations.","date":"2011","source":"Seminars in thrombosis and hemostasis","url":"https://pubmed.ncbi.nlm.nih.gov/22102272","citation_count":10,"is_preprint":false},{"pmid":"36794499","id":"PMC_36794499","title":"ANKRD26 is a new regulator of type I cytokine receptor signaling in normal and pathological hematopoiesis.","date":"2023","source":"Haematologica","url":"https://pubmed.ncbi.nlm.nih.gov/36794499","citation_count":9,"is_preprint":false},{"pmid":"32618208","id":"PMC_32618208","title":"Inherited Thrombocytopenia Caused by Germline ANKRD26 Mutation Should Be Considered in Young Patients With Suspected Myelodysplastic Syndrome.","date":"2020","source":"Journal of investigative medicine high impact case reports","url":"https://pubmed.ncbi.nlm.nih.gov/32618208","citation_count":9,"is_preprint":false},{"pmid":"32659145","id":"PMC_32659145","title":"Relation between mutations in the 5' UTR of ANKRD26 gene and inherited thrombocytopenia with predisposition to myeloid malignancies. An Egyptian study.","date":"2020","source":"Platelets","url":"https://pubmed.ncbi.nlm.nih.gov/32659145","citation_count":6,"is_preprint":false},{"pmid":"28698781","id":"PMC_28698781","title":"Idiopathic Pulmonary Embolism in a case of Severe Family ANKRD26 Thrombocytopenia.","date":"2017","source":"Mediterranean journal of hematology and infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/28698781","citation_count":5,"is_preprint":false},{"pmid":"37852929","id":"PMC_37852929","title":"Analysis of clinical characteristics and treatment efficacy in two pediatric cases of ANKRD26-related thrombocytopenia.","date":"2023","source":"Platelets","url":"https://pubmed.ncbi.nlm.nih.gov/37852929","citation_count":3,"is_preprint":false},{"pmid":"38757516","id":"PMC_38757516","title":"Inherited thrombocytopenia associated with a variant in the FLI1 binding site in the 5' UTR of ANKRD26.","date":"2024","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38757516","citation_count":3,"is_preprint":false},{"pmid":"32944898","id":"PMC_32944898","title":"A novel RUNX1 mutation with ANKRD26 dysregulation is related to thrombocytopenia in a sporadic form of myelodysplastic syndrome.","date":"2020","source":"Aging clinical and experimental research","url":"https://pubmed.ncbi.nlm.nih.gov/32944898","citation_count":3,"is_preprint":false},{"pmid":"36753059","id":"PMC_36753059","title":"Novel ANKRD26 and PDGFRB gene mutations in pediatric case of non-Langerhans cell histiocytosis: Case report and literature review.","date":"2023","source":"Journal of cutaneous pathology","url":"https://pubmed.ncbi.nlm.nih.gov/36753059","citation_count":3,"is_preprint":false},{"pmid":"32979630","id":"PMC_32979630","title":"Generation of the human induced pluripotent stem cell line (SHAMUi001-A) carrying the heterozygous c.-128G>T mutation in the 5'-UTR of the ANKRD26 gene.","date":"2020","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/32979630","citation_count":3,"is_preprint":false},{"pmid":"27108925","id":"PMC_27108925","title":"ANKRD26 normocytic thrombocytopenia: a family report.","date":"2016","source":"Annales de biologie clinique","url":"https://pubmed.ncbi.nlm.nih.gov/27108925","citation_count":3,"is_preprint":false},{"pmid":"37176611","id":"PMC_37176611","title":"A Novel Constitutional t(3;8)(p26;q21) and ANKRD26 and SRP72 Variants in a Child with Myelodysplastic Neoplasm: Clinical Implications.","date":"2023","source":"Journal of clinical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37176611","citation_count":2,"is_preprint":false},{"pmid":"31281687","id":"PMC_31281687","title":"Multiple Myeloma in a Patient with ANKRD26-Related Thrombocytopenia Successfully Treated with Combination Therapy and Autologous Stem Cell Transplant.","date":"2019","source":"Case reports in hematology","url":"https://pubmed.ncbi.nlm.nih.gov/31281687","citation_count":2,"is_preprint":false},{"pmid":"40806462","id":"PMC_40806462","title":"Chromosomal Deletion Involving ANKRD26 Leads to Expression of a Fusion Protein Responsible for ANKRD26-Related Thrombocytopenia.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40806462","citation_count":2,"is_preprint":false},{"pmid":"40170493","id":"PMC_40170493","title":"Modeling ANKRD26 5'-UTR mutation-related thrombocytopenia.","date":"2025","source":"Disease models & mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/40170493","citation_count":1,"is_preprint":false},{"pmid":"39212265","id":"PMC_39212265","title":"Impact of thrombocytopenia-associated c.-118C>T and c.-140C>G ANKRD26 5'UTR variants in three-generational pedigree.","date":"2024","source":"Platelets","url":"https://pubmed.ncbi.nlm.nih.gov/39212265","citation_count":1,"is_preprint":false},{"pmid":"38493476","id":"PMC_38493476","title":"Ankrd26 is a retinoic acid-responsive plasma membrane-binding and -shaping protein critical for proper cell differentiation.","date":"2024","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/38493476","citation_count":1,"is_preprint":false},{"pmid":"37065357","id":"PMC_37065357","title":"ANKRD26 Gene Variant of Uncertain Significance in a Patient With Acute Myeloid Leukemia.","date":"2023","source":"Cureus","url":"https://pubmed.ncbi.nlm.nih.gov/37065357","citation_count":1,"is_preprint":false},{"pmid":"39791724","id":"PMC_39791724","title":"Inherited Thrombocytopenia Related Genes: GPS2 Mediates the Interplay Between ANKRD26 and ETV6.","date":"2024","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/39791724","citation_count":0,"is_preprint":false},{"pmid":"41538704","id":"PMC_41538704","title":"Single-cell profiling of ANKRD26 thrombocytopenia reveals progenitor expansion and polyploid apoptosis via JUNB-p21.","date":"2026","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/41538704","citation_count":0,"is_preprint":false},{"pmid":"40954090","id":"PMC_40954090","title":"Differential transcript level of ANKRD26 and clinical phenotype among the ANKRD26 variants in the Japanese registry for congenital thrombocytopenia.","date":"2025","source":"British journal of haematology","url":"https://pubmed.ncbi.nlm.nih.gov/40954090","citation_count":0,"is_preprint":false},{"pmid":"40863182","id":"PMC_40863182","title":"ANKRD26 Gene Mutation and Thrombocytopenia-Is the Risk of Malignancy Dependent on the Mutation Variant?","date":"2025","source":"Hematology reports","url":"https://pubmed.ncbi.nlm.nih.gov/40863182","citation_count":0,"is_preprint":false},{"pmid":"41643484","id":"PMC_41643484","title":"Generation of an induced pluripotent stem cell line CGOi001-A from a patient with hereditary thrombocytopenia and a germline ANKRD26 mutation.","date":"2026","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/41643484","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.08.27.609375","title":"The PIDDosome controls cardiomyocyte polyploidization during postnatal heart development","date":"2024-08-28","source":"bioRxiv","url":"https://doi.org/10.1101/2024.08.27.609375","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":22804,"output_tokens":3630,"usd":0.061431},"stage2":{"model":"claude-opus-4-6","input_tokens":7041,"output_tokens":2938,"usd":0.162983},"total_usd":0.224414,"stage1_batch_id":"msgbatch_01TqNM6p6FsoMBT2jzQTwKBr","stage2_batch_id":"msgbatch_01Ya473eco8sTHbvRymQaU8o","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"THC2-associated mutations in the 5' UTR of ANKRD26 disrupt binding of transcription factors RUNX1 and FLI1, preventing ANKRD26 silencing during late megakaryopoiesis. Persistent ANKRD26 expression increases signaling via the TPO/MPL pathway and impairs proplatelet formation; ERK inhibition rescues proplatelet formation in vitro.\",\n      \"method\": \"Patient-derived megakaryocytes, reporter assays, RUNX1/FLI1 ChIP/binding assays, ERK inhibitor rescue experiments\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in primary patient cells with functional rescue; independently supported by later studies\",\n      \"pmids\": [\"24430186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ANKRD26 localizes to centriolar distal appendages and recruits PIDD1 to this location; this interaction is required for PIDDosome activation (Caspase-2 cleavage of MDM2) following centrosome amplification, linking extra centrosomes to p53 stabilization and cell cycle arrest.\",\n      \"method\": \"Genome-wide screen, Co-IP, immunofluorescence localization, Caspase-2 activity assays, PIDD1 autoproteolysis assays, genetic knockouts\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — replicated independently by two labs in the same journal issue with reciprocal Co-IP, localization, and functional readouts\",\n      \"pmids\": [\"33350486\", \"33350495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TALPID3 and ANKRD26 form a complex with FBF1 at transition fibers (distal appendages) to regulate cilia gating; co-depletion of TALPID3 and ANKRD26 specifically impairs FBF1 recruitment to transition fibers in both C. elegans and mammalian cells.\",\n      \"method\": \"Forward genetic screen in C. elegans, Co-IP, immunofluorescence, genetic epistasis (double depletion), mammalian cell validation\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ortholog function confirmed in mammalian cells, multiple orthogonal methods including genetic epistasis and reciprocal Co-IP\",\n      \"pmids\": [\"32366837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ANKRD26 interacts with and modulates the activity of three homodimeric type I cytokine receptors (MPL, EPOR, G-CSFR); elevated ANKRD26 prevents receptor internalization, leading to increased downstream signaling and cytokine hypersensitivity in erythroid, megakaryocyte, and granulocyte progenitors.\",\n      \"method\": \"Co-IP in cell lines and primary patient cells, patient-derived iPSC models, receptor internalization assays, cytokine sensitivity assays\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple human-relevant in vitro models, Co-IP, and functional receptor internalization assays\",\n      \"pmids\": [\"36794499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Partial inactivation of Ankrd26 in mice causes extreme obesity, insulin resistance, hyperphagia, and gigantism; the protein is expressed in hypothalamic arcuate and ventromedial nuclei, and loss leads to elevated phospho-Akt and mTOR in enlarged hearts.\",\n      \"method\": \"Mutant mouse model (partial gene inactivation), metabolic phenotyping, immunohistochemistry, western blot for phospho-Akt/mTOR\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo loss-of-function with multiple phenotypic readouts and biochemical pathway analysis\",\n      \"pmids\": [\"18162531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Ankrd26 disruption in mouse embryonic fibroblasts enhances adipogenesis via constitutive ERK activation; MEK inhibition blocks ERK activation and reduces adipogenesis induction, placing ANKRD26 upstream of ERK in the adipogenic pathway.\",\n      \"method\": \"Ankrd26-/- MEF adipogenesis assays, gene expression analysis, MEK inhibitor rescue experiments, western blot for phospho-ERK\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with defined phenotype, pharmacological rescue, and pathway placement\",\n      \"pmids\": [\"21669876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ANKRD26 interacts with TRIO, GPS2, DIPA, and HMMR (identified by yeast two-hybrid and co-immunoprecipitation); the C-terminus of ANKRD26 causes nuclear GPS2 and DIPA to translocate to the cytoplasm; knockdown of each partner increases adipogenesis in 3T3-L1 cells.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, subcellular localization by microscopy, siRNA knockdown with adipogenesis readout\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP/Y2H with functional follow-up in single study\",\n      \"pmids\": [\"22666460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Disruption of Ankrd26 causes defects in primary cilia in CNS regions controlling appetite and energy homeostasis, representing a novel ciliopathy mechanism underlying hyperphagia and obesity in Ankrd26 knockout mice.\",\n      \"method\": \"Ankrd26-/- mouse model, histological and electron microscopic analysis of primary cilia in CNS\",\n      \"journal\": \"Brain structure & function\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo loss-of-function with direct morphological assessment of cilia, single study\",\n      \"pmids\": [\"24633808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"5' UTR mutations in ANKRD26 likely enhance ANKRD26 expression rather than cause haploinsufficiency, as demonstrated by luciferase reporter assay showing increased promoter activity with THC2-associated mutations.\",\n      \"method\": \"Luciferase reporter assay with 5' UTR constructs carrying THC2 mutations\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — reporter assay in single study, consistent with later functional data\",\n      \"pmids\": [\"21211618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"N-terminal truncating ANKRD26 coding mutations (c.3G>A and c.105C>G) produce stable isoforms with strong ability to activate MAPK/ERK signaling, and are associated with ANKRD26 overexpression in AML patients.\",\n      \"method\": \"Patient cell functional studies, western blot, ERK signaling assays\",\n      \"journal\": \"Journal of hematology & oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single study, cell-based functional assays with patient samples\",\n      \"pmids\": [\"28100250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ANKRD26 uses an N-terminal amphipathic structure for plasma membrane binding and bending, self-associates to form clusters at the plasma membrane in response to retinoic acid, and is required for retinoic acid/BDNF-induced neuroblastoma differentiation; an AML-associated N-terminal truncating mutation abolishes membrane association and impairs differentiation.\",\n      \"method\": \"Subcellular localization by live imaging, gain-of-function and loss-of-function/rescue experiments, structural domain mutagenesis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods including mutagenesis and rescue experiments, single study\",\n      \"pmids\": [\"38493476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A large complex structural variant (paired-duplication inversion) creates a pathogenic gain-of-function WAC-ANKRD26 fusion transcript that causes inherited thrombocytopenia resembling THC2, demonstrating that persistent ANKRD26 expression (via fusion) during hematopoietic differentiation is the pathogenic mechanism.\",\n      \"method\": \"Long-read whole-genome sequencing, functional studies of fusion transcript expression and effect on ANKRD26 silencing\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — long-read sequencing plus functional validation, single study\",\n      \"pmids\": [\"33857290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ANKRD26 interacts with ETV6 and retains it in the cytoplasm; GPS2 (a component of the NCoR complex) binds both ANKRD26 and ETV6, mediating their interaction; ANKRD26 overexpression deregulates ETV6 transcriptional repression, revealing an ANKRD26-ETV6-GPS2 axis.\",\n      \"method\": \"Co-IP, subcellular localization studies, transcriptional reporter assays\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP and localization with functional transcriptional readout, single study\",\n      \"pmids\": [\"39791724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A novel 5' UTR variant (c.-107C>T) in the FLI1 binding site (not the RUNX1 site) of ANKRD26 disrupts FLI1 binding, sustains ANKRD26 expression in differentiating megakaryocytes, and impairs proplatelet formation, extending the functional regulatory region of ANKRD26.\",\n      \"method\": \"PBMCs differentiation assays, reporter assay, platelet ANKRD26 expression by qPCR, megakaryocyte functional studies\",\n      \"journal\": \"Clinical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — multiple methods but single study, mechanistically confirmatory of established RUNX1/FLI1 regulatory mechanism\",\n      \"pmids\": [\"38757516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Elevated ANKRD26 induces apoptosis in polyploid megakaryocytes via JUNB-mediated transcriptional activation of CDKN1A (p21), operating independently of the canonical p53-PIDDosome axis; ANKRD26 protein localizes to the centrosome in megakaryocytes.\",\n      \"method\": \"Single-cell transcriptomics of patient bone marrow, confocal imaging for centrosome localization, mechanistic pathway analysis in primary megakaryocytes\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multipatient single-cell analysis with orthogonal imaging, single study\",\n      \"pmids\": [\"41538704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PIDDosome activation requires ANKRD26 to target PIDD1 to mother centrioles in cardiomyocytes during postnatal heart development; this limits CM polyploidization in a p53-independent but p21/Cdkn1a-dependent manner.\",\n      \"method\": \"Genetic deletion of PIDDosome components, nuclear RNA sequencing, DNA content analyses, postnatal developmental time course experiments in mice\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo genetic experiments with multiple readouts, but preprint\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"ANKRD26 is a plasma membrane- and centrosome-associated ankyrin repeat protein that (1) is transcriptionally silenced in late megakaryopoiesis by RUNX1/FLI1 binding to its 5' UTR, and 5' UTR mutations that prevent this silencing cause persistent ANKRD26 expression, which hyperactivates MAPK/ERK signaling and prevents proplatelet formation via sustained TPO/MPL, EPOR, and G-CSFR signaling by blocking receptor internalization; (2) localizes to centriolar distal appendages where it recruits PIDD1 to activate the PIDDosome (Caspase-2/MDM2/p53 axis) as a safeguard against centrosome amplification; (3) coordinates with TALPID3 to recruit FBF1 to transition fibers for cilia gating; (4) regulates adipogenesis and appetite via hypothalamic expression and ERK-dependent signaling; and (5) interacts with partners including TRIO, GPS2, HMMR, DIPA, and ETV6, with GPS2 mediating an ANKRD26-ETV6 cytoplasmic retention axis relevant to thrombocytopenia predisposition to leukemia.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ANKRD26 is an ankyrin repeat protein that functions at centrosomes and the plasma membrane to integrate cytokine receptor signaling, centrosome surveillance, and ciliogenesis. During megakaryopoiesis, ANKRD26 is normally silenced by RUNX1/FLI1 binding to its 5′ UTR; gain-of-function mutations that prevent this silencing cause persistent ANKRD26 expression, which blocks internalization of type I cytokine receptors (MPL, EPOR, G-CSFR), hyperactivates MAPK/ERK signaling, and impairs proplatelet formation, causing thrombocytopenia 2 (THC2) with predisposition to myeloid malignancies [PMID:24430186, PMID:36794499, PMID:33857290]. At centriolar distal appendages, ANKRD26 recruits PIDD1 to activate the PIDDosome–Caspase-2–MDM2–p53 axis as a checkpoint against centrosome amplification, and cooperates with TALPID3 to recruit FBF1 for cilia gating [PMID:33350486, PMID:32366837]. ANKRD26 also uses an N-terminal amphipathic structure for plasma membrane binding and self-assembly, and its loss in mice causes obesity, hyperphagia, enhanced adipogenesis via constitutive ERK activation, and CNS ciliary defects [PMID:38493476, PMID:18162531, PMID:21669876, PMID:24633808].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"The first in vivo loss-of-function study established that ANKRD26 is required for metabolic homeostasis, as partial inactivation caused extreme obesity, hyperphagia, and insulin resistance linked to elevated Akt/mTOR signaling in mice.\",\n      \"evidence\": \"Mutant mouse model with metabolic phenotyping, hypothalamic immunohistochemistry, and western blot\",\n      \"pmids\": [\"18162531\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which hypothalamic ANKRD26 controls appetite not defined\", \"Direct molecular target in arcuate/ventromedial nuclei unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"ANKRD26 was placed upstream of MAPK/ERK in adipogenesis: Ankrd26 disruption constitutively activated ERK and enhanced adipocyte differentiation, while separate reporter assays showed that THC2-associated 5′ UTR mutations increase rather than decrease ANKRD26 expression.\",\n      \"evidence\": \"Ankrd26−/− MEF adipogenesis assays with MEK inhibitor rescue; luciferase reporter assays with THC2 5′ UTR constructs\",\n      \"pmids\": [\"21669876\", \"21211618\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism connecting ANKRD26 to ERK activation (direct or indirect) not resolved\", \"Reporter assays did not identify the specific trans-acting factors\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identification of direct protein partners (TRIO, GPS2, DIPA, HMMR) revealed that ANKRD26 sequesters nuclear factors to the cytoplasm and that each partner functionally opposes adipogenesis.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, subcellular localization, siRNA knockdown in 3T3-L1 cells\",\n      \"pmids\": [\"22666460\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Y2H interactions lack reciprocal validation in some cases\", \"Stoichiometry and whether these form a single complex or separate binary interactions unknown\", \"Relevance beyond adipogenesis not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"The disease mechanism for THC2 was resolved: 5′ UTR mutations disrupt RUNX1/FLI1 binding, preventing transcriptional silencing of ANKRD26 during late megakaryopoiesis; persistent expression hyperactivates TPO/MPL–ERK signaling and blocks proplatelet formation, with ERK inhibition rescuing the defect.\",\n      \"evidence\": \"Patient-derived megakaryocytes, ChIP/binding assays for RUNX1/FLI1, ERK inhibitor rescue\",\n      \"pmids\": [\"24430186\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ANKRD26 directly binds MPL or acts via an adaptor not determined\", \"Mechanism of leukemia predisposition not explained by ERK hyperactivation alone\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"The obesity phenotype was connected to ciliogenesis: Ankrd26 knockout mice showed defective primary cilia in CNS appetite-regulating centers, establishing a ciliopathy mechanism for the metabolic phenotype.\",\n      \"evidence\": \"Histological and electron microscopic analysis of cilia in Ankrd26−/− mouse CNS\",\n      \"pmids\": [\"24633808\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular role of ANKRD26 in cilia assembly versus maintenance not distinguished\", \"Whether ciliary defects are cell-autonomous not tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Two independent studies established ANKRD26 as a centriolar distal appendage protein that recruits PIDD1 to activate the PIDDosome checkpoint against centrosome amplification, and a parallel study showed ANKRD26 cooperates with TALPID3 to recruit FBF1 to transition fibers for cilia gating.\",\n      \"evidence\": \"Genome-wide screens, Co-IP, immunofluorescence, Caspase-2 activity assays, genetic epistasis in C. elegans and mammalian cells\",\n      \"pmids\": [\"33350486\", \"33350495\", \"32366837\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ANKRD26 is itself recruited to distal appendages not known\", \"Whether cilia gating and PIDDosome functions are coordinated or independent unclear\", \"Structural basis of ANKRD26–PIDD1 interaction not resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The receptor-level mechanism was clarified: elevated ANKRD26 directly interacts with and prevents internalization of MPL, EPOR, and G-CSFR, explaining cytokine hypersensitivity across multiple hematopoietic lineages in THC2.\",\n      \"evidence\": \"Co-IP in cell lines and patient iPSC-derived cells, receptor internalization and cytokine sensitivity assays\",\n      \"pmids\": [\"36794499\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding interface on the receptors not mapped\", \"Whether ANKRD26 blocks ubiquitin-dependent or clathrin-dependent internalization specifically is unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"ANKRD26 was shown to bind and bend membranes via an N-terminal amphipathic structure, self-assemble into plasma membrane clusters in response to retinoic acid, and be required for neuroblastoma differentiation — with an AML-linked truncation abolishing membrane association.\",\n      \"evidence\": \"Live imaging, domain mutagenesis, gain/loss-of-function and rescue experiments in neuroblastoma cells\",\n      \"pmids\": [\"38493476\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Lipid specificity of membrane binding not characterized\", \"Relevance of membrane remodeling to megakaryocyte biology not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"An ANKRD26–GPS2–ETV6 cytoplasmic retention axis was identified, explaining how ANKRD26 overexpression deregulates the tumor suppressor ETV6, providing a mechanistic link between THC2 and leukemia predisposition.\",\n      \"evidence\": \"Co-IP, subcellular localization, transcriptional reporter assays\",\n      \"pmids\": [\"39791724\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single study without independent replication\", \"In vivo relevance to leukemogenesis not demonstrated\", \"Whether GPS2 bridges or stabilizes the ANKRD26–ETV6 interaction directly is unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"In polyploid megakaryocytes, elevated ANKRD26 drives apoptosis through JUNB-mediated CDKN1A (p21) induction independently of the canonical p53–PIDDosome pathway, revealing a p53-independent arm of ANKRD26 centrosomal signaling.\",\n      \"evidence\": \"Single-cell transcriptomics of patient bone marrow, confocal centrosome imaging in megakaryocytes\",\n      \"pmids\": [\"41538704\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking centrosomal ANKRD26 to JUNB activation not defined\", \"Single study requiring independent confirmation\", \"Relationship to PIDDosome-dependent p21 induction in cardiomyocytes unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: how ANKRD26 is recruited to distal appendages, whether its membrane-remodeling and centrosome functions are coordinated, the structural basis of receptor interaction and internalization blockade, and the mechanistic pathway from ANKRD26 overexpression to myeloid transformation.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of ANKRD26 or its complexes exists\", \"Direct in vivo demonstration of leukemia initiation by ANKRD26 overexpression is lacking\", \"Relative contribution of PIDDosome-dependent versus JUNB/p21-dependent pathways in megakaryocytes not delineated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 3, 5]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 6, 12]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 10]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [1, 14]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [2, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3, 5, 9]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [2, 7]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 10]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 9, 11]}\n    ],\n    \"complexes\": [\n      \"PIDDosome\"\n    ],\n    \"partners\": [\n      \"PIDD1\",\n      \"GPS2\",\n      \"TRIO\",\n      \"HMMR\",\n      \"ETV6\",\n      \"FBF1\",\n      \"TALPID3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}