{"gene":"ATXN10","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2003,"finding":"The (ATTCT)n.(AGAAT)n repeat in the ATXN10 gene forms an unpaired DNA structure under torsional stress (supercoiling), and this unpaired structure can function as an aberrant replication origin, supporting complete plasmid replication in a HeLa cell extract.","method":"Two-dimensional gel electrophoresis, atomic force microscopy, chemical probing, and in vitro replication assay in HeLa cell extract","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal biochemical methods (2D gels, AFM, chemical probing, in vitro replication reconstitution) in a single rigorous study","pmids":["12589756"],"is_preprint":false},{"year":2007,"finding":"Expanded (ATTCT)n tracts at the ATX10 locus act as functional DNA unwinding elements (DUEs) and elevate replication origin activity; expanded ATX10 loci in patient-derived cells show increased origin activity compared to the wild-type locus, and ectopic chimeric c-myc replicators containing (ATTCT)27 or (ATTCT)48 (but not shorter tracts) drive length-dependent repeat expansion by ~250 population doublings.","method":"Replication origin assay in patient-derived cells; ectopic replicator cell lines with ATX10 DUE substitutions; repeat-length instability assay over population doublings","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro/cell-based reconstitution of replication origin activity with defined length-dependent thresholds, corroborated by patient-derived cell data","pmids":["17846122"],"is_preprint":false},{"year":2005,"finding":"Reduced expression of ATXN10/E46L in primary cerebellar and cortical neuronal cultures by siRNA causes increased apoptosis, indicating that ATXN10 protein expression is required for neuronal survival.","method":"siRNA knockdown in primary neuronal cultures with apoptosis readout","journal":"Cerebellum (London, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — loss-of-function with defined cellular phenotype (apoptosis) in primary neurons, single lab, single method reported in a review abstract","pmids":["15895557"],"is_preprint":false},{"year":2011,"finding":"The spliced intron-9 RNA containing the expanded AUUCU repeat aggregates in SCA10 cells and sequesters hnRNP K; hnRNP K sequestration triggers translocation of protein kinase Cδ (PKCδ) to mitochondria, leading to caspase-3 activation and apoptosis. Expression of (ATTCT)500 in the 3'UTR of a transgene in mice recapitulates this pathway and causes neuronal loss, gait abnormalities, and increased seizure susceptibility.","method":"SCA10 cell model (RNA foci/sequestration), transgenic mouse model with expanded repeat in 3'UTR, molecular and cellular analysis of PKCδ, caspase-3","journal":"Journal of neuroscience research","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell model plus independent transgenic mouse validation, two orthogonal model systems, specific pathway components (hnRNP K, PKCδ, caspase-3) identified","pmids":["22065565"],"is_preprint":false},{"year":2015,"finding":"r(AUUCU) repeat RNA from the ATXN10 expanded intron adopts an A-form hairpin structure with 3×3 nucleotide (5')UCU(3')/(3')UCU(5') internal loops closed by AU pairs; molecular dynamics simulations show that loop-closing pairs can transiently form single-stranded conformations, providing structural basis for protein (e.g., hnRNP K) recruitment.","method":"X-ray crystallography (2.8 Å crystal structure) and molecular dynamics simulations","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure at 2.8 Å with MD simulation validation, single lab but rigorous structural method","pmids":["26039897"],"is_preprint":false},{"year":2021,"finding":"ATXN10 protein is essential for embryonic development and adult tissue homeostasis: congenital loss causes embryonic lethality (~E10.5) with pericardial effusion and cardiac trabeculation defects; myocardium-specific loss (cTnT-Cre) causes lethal cardiac malformations; systemic postnatal deletion causes rapid epithelial-to-mesenchymal transition (EMT) in kidney and pancreas, pancreatic acinar-to-ductal metaplasia, glucose homeostasis defects, and lethality within weeks. ATXN10 protein localizes around the base of the cilium and in the cytosol, but its loss does not overtly affect cilia formation or morphology.","method":"Congenital and conditional knockout mouse models (Tie2-Cre, cTnT-Cre, inducible Cagg-CreER); histopathology, immunofluorescence/localization, glucose homeostasis assays","journal":"Frontiers in cell and developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple independent conditional KO lines with distinct tissue-specific drivers, defined cellular phenotypes and subcellular localization, single study but multiple orthogonal genetic and histological approaches","pmids":["34970537"],"is_preprint":false}],"current_model":"ATXN10 encodes a cytoplasmic protein (also detectable at the cilium base) that is essential for embryonic cardiac development, adult epithelial integrity, and neuronal survival; its expanded intronic ATTCT repeat forms an unpaired DNA structure that acts as an aberrant replication origin driving repeat instability, while the resulting expanded AUUCU repeat RNA (structurally characterized as an A-form hairpin with dynamic internal loops) sequesters hnRNP K, triggering PKCδ mitochondrial translocation, caspase-3 activation, and apoptosis in a toxic RNA gain-of-function mechanism."},"narrative":{"mechanistic_narrative":"ATXN10 encodes a cytoplasmic protein, also detectable around the base of the cilium, that is essential for embryonic cardiac development and adult tissue homeostasis: congenital loss causes embryonic lethality with cardiac trabeculation defects, myocardium-specific deletion produces lethal cardiac malformations, and systemic postnatal deletion drives epithelial-to-mesenchymal transition in kidney and pancreas with acinar-to-ductal metaplasia and glucose homeostasis defects, though its loss does not overtly perturb cilia formation [PMID:34970537]. In neurons, ATXN10 protein expression is required for survival, as its knockdown increases apoptosis in primary cerebellar and cortical cultures [PMID:15895557]. Separately, the gene harbors an intronic (ATTCT)n.(AGAAT)n repeat that, under torsional stress, forms an unpaired DNA structure functioning as an aberrant replication origin [PMID:12589756]; expanded tracts act as length-dependent DNA unwinding elements that elevate origin activity and drive repeat expansion in patient-derived and ectopic-replicator cells [PMID:17846122]. The expanded transcript is the basis of a toxic RNA gain-of-function disease mechanism: the spliced intron-9 RNA bearing the expanded AUUCU repeat aggregates and sequesters hnRNP K, triggering PKCδ translocation to mitochondria, caspase-3 activation, and apoptosis, a pathway recapitulated in transgenic mice expressing (ATTCT)500 that develop neuronal loss, gait abnormalities, and seizure susceptibility [PMID:22065565]. The repeat RNA adopts an A-form hairpin with periodic UCU/UCU internal loops whose loop-closing pairs transiently sample single-stranded conformations, providing a structural basis for protein recruitment such as hnRNP K binding [PMID:26039897].","teleology":[{"year":2003,"claim":"It was unknown how the ATXN10 repeat could destabilize; demonstrating that the repeat forms an unpaired DNA structure capable of acting as a replication origin established a structural mechanism for repeat-driven genomic events.","evidence":"2D gel electrophoresis, atomic force microscopy, chemical probing, and in vitro replication in HeLa cell extract","pmids":["12589756"],"confidence":"High","gaps":["Did not address whether origin activity occurs at the endogenous chromosomal locus in vivo","No link yet to repeat expansion dynamics"]},{"year":2005,"claim":"The cellular role of the normal ATXN10 protein was unclear; knockdown in primary neurons showing increased apoptosis established that ATXN10 protein expression is required for neuronal survival.","evidence":"siRNA knockdown in primary cerebellar and cortical neuronal cultures with apoptosis readout","pmids":["15895557"],"confidence":"Medium","gaps":["Single lab, single method reported in a review abstract","Molecular pathway of survival not defined","No rescue or specificity controls described"]},{"year":2007,"claim":"Whether repeat length governs instability was unresolved; showing that expanded tracts act as DNA unwinding elements elevating origin activity and driving length-dependent expansion connected aberrant replication to repeat instability.","evidence":"Replication origin assays in patient-derived cells and ectopic chimeric c-myc replicator cell lines with defined repeat-length instability tracking over population doublings","pmids":["17846122"],"confidence":"High","gaps":["Mechanism by which longer tracts increase origin firing not resolved at nucleotide level","Cellular factors mediating expansion not identified"]},{"year":2011,"claim":"The disease mechanism of the expansion was unknown; identifying hnRNP K sequestration by AUUCU RNA leading to PKCδ mitochondrial translocation, caspase-3 activation, and apoptosis established a toxic RNA gain-of-function pathway.","evidence":"SCA10 cell model with RNA foci/sequestration analysis plus a transgenic mouse expressing (ATTCT)500 in a 3'UTR","pmids":["22065565"],"confidence":"High","gaps":["Whether hnRNP K sequestration is the sole trigger of the apoptotic cascade not established","Relationship between RNA toxicity and the protein's normal survival role unaddressed"]},{"year":2015,"claim":"The structural basis for protein recruitment by the repeat RNA was undefined; the A-form hairpin crystal structure with dynamic UCU/UCU internal loops provided a mechanistic rationale for how the RNA presents binding surfaces to proteins.","evidence":"2.8 Å X-ray crystal structure and molecular dynamics simulations of r(AUUCU) repeat RNA","pmids":["26039897"],"confidence":"High","gaps":["Direct structural evidence of hnRNP K bound to the RNA not provided","Structure of full-length expanded transcript not determined"]},{"year":2021,"claim":"The physiological function of ATXN10 protein beyond neurons was unknown; conditional knockouts established it as essential for cardiac development and adult epithelial homeostasis, with cytosolic and ciliary-base localization.","evidence":"Congenital and tissue-specific conditional knockout mice (Tie2-Cre, cTnT-Cre, inducible Cagg-CreER) with histopathology, immunofluorescence, and glucose homeostasis assays","pmids":["34970537"],"confidence":"High","gaps":["Molecular activity of ATXN10 protein not defined","Mechanistic link between cytosolic/ciliary-base localization and the EMT and cardiac phenotypes unresolved","Direct binding partners of the protein not identified"]},{"year":null,"claim":"The biochemical/molecular function of the ATXN10 protein and how its loss-of-function phenotypes relate to the expansion-driven RNA toxicity remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No defined enzymatic or binding activity for the protein","No identified direct protein partners or substrates","Unclear whether disease involves protein loss-of-function in addition to RNA gain-of-function"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[5]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[2,3]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[5]}],"complexes":[],"partners":["HNRNPK"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UBB4","full_name":"Ataxin-10","aliases":["Brain protein E46 homolog","Spinocerebellar ataxia type 10 protein"],"length_aa":475,"mass_kda":53.5,"function":"May play a role in the regulation of cytokinesis (PubMed:21857149, PubMed:25666058). May play a role in signaling by stimulating protein glycosylation. Induces neuritogenesis by activating the Ras-MAP kinase pathway and is necessary for the survival of cerebellar neurons (By similarity). Does not appear to play a major role in ciliogenesis (By similarity)","subcellular_location":"Cytoplasm, perinuclear region; Midbody; Cytoplasm, cytoskeleton, cilium basal body; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriole","url":"https://www.uniprot.org/uniprotkb/Q9UBB4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ATXN10","classification":"Not Classified","n_dependent_lines":457,"n_total_lines":1208,"dependency_fraction":0.3783112582781457},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000130638","cell_line_id":"CID001673","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":2}],"interactors":[{"gene":"ABCE1","stoichiometry":0.2},{"gene":"PPP1R12A","stoichiometry":0.2},{"gene":"SMARCA4","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001673","total_profiled":1310},"omim":[{"mim_id":"620208","title":"SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 33; SCAR33","url":"https://www.omim.org/entry/620208"},{"mim_id":"620204","title":"RNA, U12 SMALL NUCLEAR; RNU12","url":"https://www.omim.org/entry/620204"},{"mim_id":"611150","title":"ATAXIN 10; ATXN10","url":"https://www.omim.org/entry/611150"},{"mim_id":"603516","title":"SPINOCEREBELLAR ATAXIA 10; SCA10","url":"https://www.omim.org/entry/603516"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Primary cilium","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ATXN10"},"hgnc":{"alias_symbol":["E46L","FLJ37990","ATX10"],"prev_symbol":["SCA10"]},"alphafold":{"accession":"Q9UBB4","domains":[{"cath_id":"1.25.10,1.20.58","chopping":"16-158","consensus_level":"medium","plddt":94.4403,"start":16,"end":158},{"cath_id":"-","chopping":"166-238","consensus_level":"medium","plddt":96.8529,"start":166,"end":238},{"cath_id":"1.25.10.10","chopping":"258-438","consensus_level":"medium","plddt":88.9009,"start":258,"end":438}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UBB4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UBB4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UBB4-F1-predicted_aligned_error_v6.png","plddt_mean":89.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ATXN10","jax_strain_url":"https://www.jax.org/strain/search?query=ATXN10"},"sequence":{"accession":"Q9UBB4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UBB4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UBB4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UBB4"}},"corpus_meta":[{"pmid":"12589756","id":"PMC_12589756","title":"Unpaired 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repeat-primed PCR assay.","date":"2004","source":"The Journal of molecular diagnostics : JMD","url":"https://pubmed.ncbi.nlm.nih.gov/15096564","citation_count":47,"is_preprint":false},{"pmid":"15895557","id":"PMC_15895557","title":"Recent progress in spinocerebellar ataxia type-10 (SCA10).","date":"2005","source":"Cerebellum (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/15895557","citation_count":44,"is_preprint":false},{"pmid":"19234597","id":"PMC_19234597","title":"Ancestral origin of the ATTCT repeat expansion in spinocerebellar ataxia type 10 (SCA10).","date":"2009","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/19234597","citation_count":42,"is_preprint":false},{"pmid":"22065565","id":"PMC_22065565","title":"Transgenic mice with SCA10 pentanucleotide repeats show motor phenotype and susceptibility to seizure: a toxic RNA gain-of-function model.","date":"2011","source":"Journal of neuroscience 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population: further exclusion of SCA dynamic repeat mutations.","date":"2012","source":"Journal of the neurological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/23026538","citation_count":6,"is_preprint":false},{"pmid":"38832639","id":"PMC_38832639","title":"Extended haplotype with rs41524547-G defines the ancestral origin of SCA10.","date":"2024","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38832639","citation_count":5,"is_preprint":false},{"pmid":"12235814","id":"PMC_12235814","title":"[Spinocerebellar ataxia type 10 (SCA10): a disease caused by a novel pentanucleotide repeat expansion].","date":"2001","source":"Rinsho shinkeigaku = Clinical neurology","url":"https://pubmed.ncbi.nlm.nih.gov/12235814","citation_count":4,"is_preprint":false},{"pmid":"31737797","id":"PMC_31737797","title":"Spinocerebellar ataxia type 10 (SCA10): Mutation analysis and common haplotype based inference suggest its rarity in Indian 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Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/41229449","citation_count":1,"is_preprint":false},{"pmid":"35103298","id":"PMC_35103298","title":"A FEMALE CASE OF SPINOCEREBELLAR ATAXIA TYPE 10 WITH SUICIDAL BEHAVIOR AND ENDOCRINPATHIES ASSOCIATED WITH A MASSIVE EXPANSION (ATTCT) OF THE GENE ATXN10.","date":"2022","source":"Actas espanolas de psiquiatria","url":"https://pubmed.ncbi.nlm.nih.gov/35103298","citation_count":1,"is_preprint":false},{"pmid":"18386626","id":"PMC_18386626","title":"[Molecular and genetic analysis of spinocerebellar ataxia type 10 (SCA10)].","date":"2008","source":"Rinsho shinkeigaku = Clinical neurology","url":"https://pubmed.ncbi.nlm.nih.gov/18386626","citation_count":0,"is_preprint":false},{"pmid":"39820777","id":"PMC_39820777","title":"ATXN10 Gene Expansions in Mexican Patients with Ataxia Without Epilepsy.","date":"2025","source":"Cerebellum (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/39820777","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16887,"output_tokens":1732,"usd":0.038321,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8594,"output_tokens":2547,"usd":0.053323,"stage2_stop_reason":"end_turn"},"total_usd":0.091644,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"The (ATTCT)n.(AGAAT)n repeat in the ATXN10 gene forms an unpaired DNA structure under torsional stress (supercoiling), and this unpaired structure can function as an aberrant replication origin, supporting complete plasmid replication in a HeLa cell extract.\",\n      \"method\": \"Two-dimensional gel electrophoresis, atomic force microscopy, chemical probing, and in vitro replication assay in HeLa cell extract\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal biochemical methods (2D gels, AFM, chemical probing, in vitro replication reconstitution) in a single rigorous study\",\n      \"pmids\": [\"12589756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Expanded (ATTCT)n tracts at the ATX10 locus act as functional DNA unwinding elements (DUEs) and elevate replication origin activity; expanded ATX10 loci in patient-derived cells show increased origin activity compared to the wild-type locus, and ectopic chimeric c-myc replicators containing (ATTCT)27 or (ATTCT)48 (but not shorter tracts) drive length-dependent repeat expansion by ~250 population doublings.\",\n      \"method\": \"Replication origin assay in patient-derived cells; ectopic replicator cell lines with ATX10 DUE substitutions; repeat-length instability assay over population doublings\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro/cell-based reconstitution of replication origin activity with defined length-dependent thresholds, corroborated by patient-derived cell data\",\n      \"pmids\": [\"17846122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Reduced expression of ATXN10/E46L in primary cerebellar and cortical neuronal cultures by siRNA causes increased apoptosis, indicating that ATXN10 protein expression is required for neuronal survival.\",\n      \"method\": \"siRNA knockdown in primary neuronal cultures with apoptosis readout\",\n      \"journal\": \"Cerebellum (London, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — loss-of-function with defined cellular phenotype (apoptosis) in primary neurons, single lab, single method reported in a review abstract\",\n      \"pmids\": [\"15895557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The spliced intron-9 RNA containing the expanded AUUCU repeat aggregates in SCA10 cells and sequesters hnRNP K; hnRNP K sequestration triggers translocation of protein kinase Cδ (PKCδ) to mitochondria, leading to caspase-3 activation and apoptosis. Expression of (ATTCT)500 in the 3'UTR of a transgene in mice recapitulates this pathway and causes neuronal loss, gait abnormalities, and increased seizure susceptibility.\",\n      \"method\": \"SCA10 cell model (RNA foci/sequestration), transgenic mouse model with expanded repeat in 3'UTR, molecular and cellular analysis of PKCδ, caspase-3\",\n      \"journal\": \"Journal of neuroscience research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell model plus independent transgenic mouse validation, two orthogonal model systems, specific pathway components (hnRNP K, PKCδ, caspase-3) identified\",\n      \"pmids\": [\"22065565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"r(AUUCU) repeat RNA from the ATXN10 expanded intron adopts an A-form hairpin structure with 3×3 nucleotide (5')UCU(3')/(3')UCU(5') internal loops closed by AU pairs; molecular dynamics simulations show that loop-closing pairs can transiently form single-stranded conformations, providing structural basis for protein (e.g., hnRNP K) recruitment.\",\n      \"method\": \"X-ray crystallography (2.8 Å crystal structure) and molecular dynamics simulations\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure at 2.8 Å with MD simulation validation, single lab but rigorous structural method\",\n      \"pmids\": [\"26039897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ATXN10 protein is essential for embryonic development and adult tissue homeostasis: congenital loss causes embryonic lethality (~E10.5) with pericardial effusion and cardiac trabeculation defects; myocardium-specific loss (cTnT-Cre) causes lethal cardiac malformations; systemic postnatal deletion causes rapid epithelial-to-mesenchymal transition (EMT) in kidney and pancreas, pancreatic acinar-to-ductal metaplasia, glucose homeostasis defects, and lethality within weeks. ATXN10 protein localizes around the base of the cilium and in the cytosol, but its loss does not overtly affect cilia formation or morphology.\",\n      \"method\": \"Congenital and conditional knockout mouse models (Tie2-Cre, cTnT-Cre, inducible Cagg-CreER); histopathology, immunofluorescence/localization, glucose homeostasis assays\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple independent conditional KO lines with distinct tissue-specific drivers, defined cellular phenotypes and subcellular localization, single study but multiple orthogonal genetic and histological approaches\",\n      \"pmids\": [\"34970537\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ATXN10 encodes a cytoplasmic protein (also detectable at the cilium base) that is essential for embryonic cardiac development, adult epithelial integrity, and neuronal survival; its expanded intronic ATTCT repeat forms an unpaired DNA structure that acts as an aberrant replication origin driving repeat instability, while the resulting expanded AUUCU repeat RNA (structurally characterized as an A-form hairpin with dynamic internal loops) sequesters hnRNP K, triggering PKCδ mitochondrial translocation, caspase-3 activation, and apoptosis in a toxic RNA gain-of-function mechanism.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ATXN10 encodes a cytoplasmic protein, also detectable around the base of the cilium, that is essential for embryonic cardiac development and adult tissue homeostasis: congenital loss causes embryonic lethality with cardiac trabeculation defects, myocardium-specific deletion produces lethal cardiac malformations, and systemic postnatal deletion drives epithelial-to-mesenchymal transition in kidney and pancreas with acinar-to-ductal metaplasia and glucose homeostasis defects, though its loss does not overtly perturb cilia formation [#5]. In neurons, ATXN10 protein expression is required for survival, as its knockdown increases apoptosis in primary cerebellar and cortical cultures [#2]. Separately, the gene harbors an intronic (ATTCT)n.(AGAAT)n repeat that, under torsional stress, forms an unpaired DNA structure functioning as an aberrant replication origin [#0]; expanded tracts act as length-dependent DNA unwinding elements that elevate origin activity and drive repeat expansion in patient-derived and ectopic-replicator cells [#1]. The expanded transcript is the basis of a toxic RNA gain-of-function disease mechanism: the spliced intron-9 RNA bearing the expanded AUUCU repeat aggregates and sequesters hnRNP K, triggering PKCδ translocation to mitochondria, caspase-3 activation, and apoptosis, a pathway recapitulated in transgenic mice expressing (ATTCT)500 that develop neuronal loss, gait abnormalities, and seizure susceptibility [#3]. The repeat RNA adopts an A-form hairpin with periodic UCU/UCU internal loops whose loop-closing pairs transiently sample single-stranded conformations, providing a structural basis for protein recruitment such as hnRNP K binding [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"It was unknown how the ATXN10 repeat could destabilize; demonstrating that the repeat forms an unpaired DNA structure capable of acting as a replication origin established a structural mechanism for repeat-driven genomic events.\",\n      \"evidence\": \"2D gel electrophoresis, atomic force microscopy, chemical probing, and in vitro replication in HeLa cell extract\",\n      \"pmids\": [\"12589756\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address whether origin activity occurs at the endogenous chromosomal locus in vivo\", \"No link yet to repeat expansion dynamics\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"The cellular role of the normal ATXN10 protein was unclear; knockdown in primary neurons showing increased apoptosis established that ATXN10 protein expression is required for neuronal survival.\",\n      \"evidence\": \"siRNA knockdown in primary cerebellar and cortical neuronal cultures with apoptosis readout\",\n      \"pmids\": [\"15895557\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, single method reported in a review abstract\", \"Molecular pathway of survival not defined\", \"No rescue or specificity controls described\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Whether repeat length governs instability was unresolved; showing that expanded tracts act as DNA unwinding elements elevating origin activity and driving length-dependent expansion connected aberrant replication to repeat instability.\",\n      \"evidence\": \"Replication origin assays in patient-derived cells and ectopic chimeric c-myc replicator cell lines with defined repeat-length instability tracking over population doublings\",\n      \"pmids\": [\"17846122\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which longer tracts increase origin firing not resolved at nucleotide level\", \"Cellular factors mediating expansion not identified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"The disease mechanism of the expansion was unknown; identifying hnRNP K sequestration by AUUCU RNA leading to PKCδ mitochondrial translocation, caspase-3 activation, and apoptosis established a toxic RNA gain-of-function pathway.\",\n      \"evidence\": \"SCA10 cell model with RNA foci/sequestration analysis plus a transgenic mouse expressing (ATTCT)500 in a 3'UTR\",\n      \"pmids\": [\"22065565\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether hnRNP K sequestration is the sole trigger of the apoptotic cascade not established\", \"Relationship between RNA toxicity and the protein's normal survival role unaddressed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The structural basis for protein recruitment by the repeat RNA was undefined; the A-form hairpin crystal structure with dynamic UCU/UCU internal loops provided a mechanistic rationale for how the RNA presents binding surfaces to proteins.\",\n      \"evidence\": \"2.8 Å X-ray crystal structure and molecular dynamics simulations of r(AUUCU) repeat RNA\",\n      \"pmids\": [\"26039897\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct structural evidence of hnRNP K bound to the RNA not provided\", \"Structure of full-length expanded transcript not determined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The physiological function of ATXN10 protein beyond neurons was unknown; conditional knockouts established it as essential for cardiac development and adult epithelial homeostasis, with cytosolic and ciliary-base localization.\",\n      \"evidence\": \"Congenital and tissue-specific conditional knockout mice (Tie2-Cre, cTnT-Cre, inducible Cagg-CreER) with histopathology, immunofluorescence, and glucose homeostasis assays\",\n      \"pmids\": [\"34970537\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular activity of ATXN10 protein not defined\", \"Mechanistic link between cytosolic/ciliary-base localization and the EMT and cardiac phenotypes unresolved\", \"Direct binding partners of the protein not identified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The biochemical/molecular function of the ATXN10 protein and how its loss-of-function phenotypes relate to the expansion-driven RNA toxicity remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No defined enzymatic or binding activity for the protein\", \"No identified direct protein partners or substrates\", \"Unclear whether disease involves protein loss-of-function in addition to RNA gain-of-function\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"HNRNPK\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}