{"gene":"HOXA13","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":1997,"finding":"A nonsense mutation converting a conserved tryptophan in the HOXA13 homeodomain to a stop codon, truncating 20 amino acids from the C-terminus, causes hand-foot-genital syndrome by likely eliminating DNA-binding capacity of the protein.","method":"Mutation identification by sequencing in an HFGS family; functional inference from homeodomain truncation","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct identification of loss-of-function mutation affecting the DNA-binding homeodomain, replicated across multiple families in subsequent studies","pmids":["9020844"],"is_preprint":false},{"year":1996,"finding":"Hoxa13 gene knockout in mice causes loss of the most anterior digit and altered morphogenesis of preaxial carpal/tarsal elements in both forelimb and hindlimb autopods; Hoxa13 and Hoxd13 act in a partially redundant manner, and double homozygous mutants almost completely lack chondrified condensations in the autopod.","method":"Targeted gene disruption (knockout), analysis of all allele combinations of Hoxa13 and Hoxd13","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic knockouts with defined skeletal phenotype, all allele combinations tested, replicated by multiple subsequent studies","pmids":["8898214"],"is_preprint":false},{"year":1997,"finding":"Hoxa13 homozygous knockout mice display agenesis of the caudal portion of Müllerian ducts, absence of presumptive urinary bladder development, and premature stenosis of umbilical arteries, leading to mid-gestational lethality; Hoxa13 and Hoxd13 act redundantly in early morphogenesis of posterior trunk structures including the cloaca.","method":"Targeted gene disruption (knockout); histological and morphological analysis of compound mutants","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic knockouts with multiple defined urogenital/digestive phenotypes, all allele combinations analyzed","pmids":["9428414"],"is_preprint":false},{"year":1995,"finding":"Misexpression of Hoxa-13 throughout the chick limb bud caused homeotic transformation of zeugopodal cartilages to a more distal (carpal/tarsal) fate and altered homophilic cell-adhesive properties of limb mesenchymal cells, causing Hoxa13-expressing cells to sort out from non-expressing cells in dissociation culture.","method":"Replication-competent retroviral misexpression in chick limb buds; in vitro cell dissociation and reassociation assays","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — gain-of-function misexpression combined with in vitro cell adhesion assays with defined phenotypic readouts","pmids":["7590231"],"is_preprint":false},{"year":2001,"finding":"In Hoxa13 mutant mice, EphA7 expression is markedly reduced in affected digits and in mutant mesenchymal micromass cultures; antibody blocking of EphA7 extracellular domain severely inhibits chondrogenic condensation of Hoxa13-expressing heterozygous cells in vitro, indicating that Hoxa13 regulates EphA7 to control mesenchymal cell adhesion and chondrogenic condensation.","method":"FACS isolation of GFP-tagged Hoxa13 mutant mesenchymal cells; in vitro micromass chondrogenic assay; antibody blocking experiments; in situ hybridization","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal loss-of-function genetics plus functional antibody blocking with defined cellular phenotype","pmids":["11684655"],"is_preprint":false},{"year":2003,"finding":"Hoxa13 is required for normal expression of Fgf8 and Bmp7 in the urethral plate epithelium; loss of Hoxa13 causes hypospadias through combined loss of Fgf8 and Bmp7 expression and ectopic noggin expression; Fgf8 supplementation restores proliferation to wild-type levels in mutant genital tubercle, and reduced Bmp7 explains closure defects through loss of apoptosis; Hoxa13 mutants also show altered androgen receptor expression.","method":"Hoxa13(GFP) mutant mouse analysis; in vitro Fgf8 supplementation rescue assay; in situ hybridization; immunohistochemistry","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function with rescue experiment, multiple orthogonal methods including supplementation assay","pmids":["12783783"],"is_preprint":false},{"year":2004,"finding":"HOXA13 directly binds novel enhancer regions of Bmp2 and Bmp7 to activate their expression in the developing autopod; endogenous HOXA13-Bmp2 and HOXA13-Bmp7 enhancer complexes were confirmed by immunoprecipitation from autopod tissue; exogenous BMP2 or BMP7 application partially rescues the Hoxa13 mutant limb phenotype.","method":"Biochemical enhancer-binding assays; chromatin immunoprecipitation from developing autopod; exogenous BMP2/BMP7 rescue of mutant limb phenotype","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro DNA binding assays, ChIP from tissue, and in vivo rescue experiment; multiple orthogonal methods","pmids":["15342482"],"is_preprint":false},{"year":2001,"finding":"Replacement of the Hoxa11 homeobox with the Hoxa13 homeobox (knock-in) confers dominant Hoxa13 function in the limbs and female reproductive tract, causing homeotic transformation of the uterus towards a cervix/vagina identity; gene chip analysis identified over 100 downstream gene expression changes consistent with Hoxa13 target genes.","method":"Homeobox-swap knock-in mouse; gene expression profiling (gene chips); histological analysis","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo homeobox swap with defined homeotic transformation phenotype plus genome-wide target gene identification","pmids":["11688568"],"is_preprint":false},{"year":2000,"finding":"Polyalanine expansions in the N-terminal region of HOXA13 cause hand-foot-genital syndrome; N-terminal sequence is strongly conserved among vertebrates and harbors multiple conserved domains shared with Drosophila AbdB; three large alanine repeats arose after divergence of reptiles from the mammalian lineage, possibly by replication slippage.","method":"PCR amplification and sequencing of HOXA13 N-terminal coding sequences across vertebrate species; comparative sequence analysis","journal":"Mammalian genome","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — comparative sequencing revealing evolutionary conservation, single method but broad taxonomic sampling","pmids":["10656931"],"is_preprint":false},{"year":2000,"finding":"Novel HOXA13 mutations causing HFGS include nonsense mutations (N-terminal to or within homeodomain), a polyalanine expansion, and a missense mutation at an invariant homeodomain residue; the missense mutation produces an exceptionally severe limb phenotype, indicating that different mutation types can act by distinct mechanisms (loss of function vs. potentially altered function).","method":"Mutation identification by sequencing in six HFGS families; clinical phenotype correlation","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple independent families with different mutation classes, phenotype-genotype correlation, but functional mechanism of missense inferred rather than directly demonstrated","pmids":["10839976"],"is_preprint":false},{"year":2002,"finding":"A specific HOXA13 mutation (HFGa13) acts as a dominant negative in vivo; overexpression of HFGa13 in chick caudal endoderm causes taillessness and severe gut/genitourinary malformations; HFGa13 negatively regulates Hoxd13 expression and antagonizes functions of endogenous Hoxa13 and Hoxd13.","method":"Retroviral overexpression in chick caudal endoderm; in situ hybridization; phenotypic analysis","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function in vivo experiment with defined phenotype, but dominant-negative mechanism inferred from phenotypic comparison rather than direct biochemical demonstration","pmids":["11830557"],"is_preprint":false},{"year":2004,"finding":"Polyalanine expansion mutations in HOXA13 (tested in mouse knock-in model, +10 alanines in third polyalanine tract) cause loss of function through reduction of steady-state protein levels in vivo, not through impaired mRNA expression or splicing; in vitro translation efficiency is normal, implicating enhanced protein degradation as the mechanism.","method":"Homologous recombination knock-in mouse; quantitative RT-PCR; western blot; in vitro translation assay","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — knock-in mouse model with mechanistic dissection using multiple orthogonal assays (RNA vs protein vs translation)","pmids":["15385446"],"is_preprint":false},{"year":2005,"finding":"HOXA13 and HOXD13 directly bind multiple conserved sites in the EphA7 promoter in vivo and in vitro, and activate EphA7 transcription; a mutation of the HOXA13/HOXD13 binding site in the EphA7 promoter abolishes transcriptional activation; the HOXD13(147L) brachydactyly-polydactyly mutation fails to bind the EphA7 promoter or transactivate it.","method":"Promoter characterization; in vivo ChIP in developing mouse limbs; in vitro transcription activation assays; mutagenesis of binding site","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — promoter binding confirmed by ChIP in vivo plus in vitro transactivation with mutagenesis, replicated across multiple Hox group 13 proteins","pmids":["16314414"],"is_preprint":false},{"year":2005,"finding":"HOXA13 interacts with all MEIS proteins (MEIS1A, MEIS1B, MEIS2, MEIS3) but not more diverged TALE superclass members; the C-terminal domain of MEIS1B (93 amino acids) is both necessary and sufficient for HOXA13 interaction; multiple HOX peptide domains contribute to MEIS binding; HOXA13 and MEIS1 coexpression occurs in developing male and female reproductive tracts.","method":"Yeast two-hybrid assays; Co-immunoprecipitation in mammalian cells; deletion mutagenesis of MEIS domains; expression analysis","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP in mammalian cells plus yeast two-hybrid with systematic deletion analysis","pmids":["15617687"],"is_preprint":false},{"year":2005,"finding":"HOXA13 binds AT-rich chromatin immunoprecipitated fragments (Hox-enriched fragments, HEFs) in NIH 3T3 cells; all HEFs augment transcription of a heterologous promoter when HOXA13 is coexpressed; multiple HOXA13 binding sites in the Enpp2 locus are necessary for full HOXA13-induced Enpp2 expression; HOXA13 upregulates Enpp2 without changing general histone acetylation at its locus.","method":"CsCl centrifugation-based chromatin purification and immunoprecipitation (ChIP); transcriptional reporter assays; AT-content analysis","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP with transcriptional validation and site mutagenesis, single lab","pmids":["16321965"],"is_preprint":false},{"year":2007,"finding":"HOXA13 homeodomain binds DNA with a novel high-affinity site (AT-rich); HOXA13 binds and represses the BMP antagonist Sostdc1 through two conserved regulatory sites in vivo (confirmed by limb ChIP); absence of HOXA13 leads to ectopic Sostdc1 expression, reduced BMP-activated gene expression, and decreased SMAD phosphorylation in the distal limb.","method":"Empirical SELEX-based DNA binding site determination; limb ChIP; in vitro reporter assays; analysis of Hoxa13 mutant limbs","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — DNA binding site empirically determined, ChIP in vivo, reporter assays with dosage dependence, confirmed in Hoxa13 mutant tissue","pmids":["17200107"],"is_preprint":false},{"year":2007,"finding":"HOXA13 directly regulates EphA6 and EphA7 expression in the genital tubercle (GT) vascular endothelia; HOXA13 binds conserved cis-regulatory elements in the EphA6 and EphA7 promoters with high affinity; GT ChIP confirms HOXA13 binding in vivo; HOXA13 activates EphA6 and EphA7 expression through these regulatory elements in vitro; loss of HOXA13 is associated with reduced EphA6/EphA7 and vascular defects in the GT.","method":"In vitro DNA-binding assays; chromatin immunoprecipitation from genital tubercle; transcriptional reporter assays in vitro","journal":"Developmental dynamics","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro binding, ChIP in vivo, reporter assays; loss-of-function phenotypic correlation","pmids":["17304517"],"is_preprint":false},{"year":2007,"finding":"HOXA13 polyalanine expansion proteins form cytoplasmic aggregates; distribution between cytoplasm and nucleus is polyalanine tract size-dependent; Hsp90 inhibitor geldanamycin reduces steady-state abundance of expanded HOXA13 proteins; wild-type HOXA13 and HOXD13 are sequestered in polyalanine expansion aggregates, explaining dominant-negative effects.","method":"COS cell transfection with polyalanine-expanded HOXA13 constructs; immunocytochemistry; geldanamycin treatment; co-aggregation assays","journal":"American journal of medical genetics. Part A","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — cellular imaging of aggregation with pharmacological manipulation, co-aggregation demonstrated, single lab","pmids":["17935235"],"is_preprint":false},{"year":2008,"finding":"HOXA13 is essential for placental labyrinth vascular formation; loss of HOXA13 alters placental endothelial cell morphology and reduces expression of Tie2 and Foxf1; HOXA13 directly binds the Tie2 and Foxf1 promoters in vivo (placental ChIP) with high affinity (Kd = 27–42 nM); HOXA13 can use bound promoter regions to activate gene expression in vitro.","method":"Hoxa13 mutant mouse analysis; microarray; ChIP from placenta; in vitro DNA binding (affinity measurement); reporter assays","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 1 / Strong — ChIP in vivo, in vitro binding quantification, reporter assays, loss-of-function with defined vascular phenotype","pmids":["18483557"],"is_preprint":false},{"year":2011,"finding":"NMR structure of the HOXA13 homeodomain (A13DBD) bound to an 11-mer DNA duplex reveals: the protein forms a dimer binding DNA with Kd of 7.5 nM; the N-terminal arm contacts the minor groove; helix 3 contacts the ATAA sequence in the major groove; N370 forms hydrogen bonds with adenine; V373 methyl groups contact T5, T6*, T7* for TAA recognition; I366 contacts T3* and T4*; R337, K343, F344 form the dimer interface. Mutants I366A, N370A, V373G reduce DNA binding and transcriptional activity; F344A weakens dimerization and reduces transcriptional activity by 76%.","method":"NMR structure determination; site-directed mutagenesis; DNA binding assays; transcriptional activity assays","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structure with functional validation by mutagenesis across multiple sites and two orthogonal functional assays","pmids":["21829694"],"is_preprint":false},{"year":2013,"finding":"HOXA13 directly regulates Aldh1a2 (the primary retinoic acid synthesizing enzyme in the limb) by binding a conserved cis-regulatory element in the Aldh1a2 locus; loss of HOXA13 reduces Aldh1a2 expression, RA signaling, and interdigital programmed cell death (IPCD); maternal RA supplementation partially rescues IPCD defects in Hoxa13 mutant hindlimbs.","method":"ChIP from limb tissue; reporter assays; RA signaling readout; maternal RA supplementation rescue in Hoxa13 mutants","journal":"Developmental dynamics","confidence":"High","confidence_rationale":"Tier 1 / Strong — ChIP plus reporter assay plus in vivo rescue experiment, multiple orthogonal validations","pmids":["23553814"],"is_preprint":false},{"year":2002,"finding":"Guttmacher syndrome is caused by a HOXA13 missense mutation in the recognition helix of the homeodomain (Q50L) combined with a 2-bp promoter deletion; the promoter deletion alone produces no detectable phenotype; the missense mutation is predicted to perturb DNA-binding properties, potentially resulting in both loss and specific gain of function.","method":"Sequencing of HOXA13 in Guttmacher syndrome family; molecular analysis of promoter deletion in isolation","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct mutation identification with functional inference; mechanistic distinction from pure loss-of-function established by genetic dissection of alleles","pmids":["11968094"],"is_preprint":false},{"year":2000,"finding":"The Hypodactyly (Hoxa13Hd) 50-bp deletion causes a translational frameshift producing a novel stable protein (HOXA13Hd) consisting of the first 25 wild-type amino acids plus 275 arginine/lysine-rich novel residues, lacking the homeodomain; HOXA13Hd localizes to the nucleus in transfected COS-7 cells; transgenic misexpression of HOXA13Hd in developing limbs produces severe proximal and distal limb reduction defects.","method":"Transcription start site mapping; immunoprecipitation; cell transfection with immunolocalization; transgenic misexpression in mouse limb","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — protein characterization, subcellular localization, in vivo transgenic gain-of-function with defined phenotype","pmids":["10625554"],"is_preprint":false},{"year":2003,"finding":"Hoxa-13 and Hoxa-11 are expressed in limb muscle precursor cells and represses MyoD expression; forced expression of Hoxa-13 in limb muscle precursors or C2C12 myoblasts causes pronounced repression of MyoD; targeted disruption of Hoxa-13 results in enhanced MyoD expression in the flexor carpi radialis muscle, confirming endogenous regulation.","method":"In ovo electroporation; C2C12 cell transfection; gene knockout with in situ hybridization","journal":"Development, growth & differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with defined molecular readout (MyoD expression), replicated across two experimental systems","pmids":["14706073"],"is_preprint":false},{"year":2010,"finding":"Surviving Hoxa13 homozygous mutant mice display missing phalanges, fused carpal/tarsal elements, and reduced metacarpal/metatarsal length; Gdf5 expression is significantly reduced and diffuse in affected carpal/tarsal anlagen, identifying Gdf5 as a potential direct HOXA13 target gene involved in skeletal element delineation; Bmp2 expression is elevated.","method":"Analysis of surviving Hoxa13(GFP) homozygous mutants; quantitative gene expression analysis; in situ hybridization","journal":"Developmental dynamics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic loss-of-function with defined molecular phenotype, but Gdf5 described as 'potential' target without direct binding confirmation","pmids":["20034107"],"is_preprint":false},{"year":2015,"finding":"HOXA13 directly regulates expression of Fgf8 and Bmp7 in the urethral plate, and is also required for the development of the glans penis vasculature; HOXA13 regulates genes required for proper androgen signaling in the genital tubercle.","method":"Hoxa13 mutant mouse; expression analysis of downstream targets; in vitro proliferation rescue with Fgf8","journal":"Genesis (New York, N.Y. : 2000)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with defined target gene changes, corroborated by functional rescue; localization data from Cre-fate mapping","pmids":["25980463"],"is_preprint":false},{"year":2015,"finding":"HoxA13 is more highly expressed in the lower uterine segment (LUS) than the fundal myometrium during pregnancy; HoxA13 upregulates transcription of PTGIS and POSTN in myometrial cells; elevated HoxA13 enhances myometrial cell contractility and cell-cell adhesion; HoxA13-regulated genes are associated with immune response, gap junction/cell adhesion, and pregnancy.","method":"RNA sequencing of human myometrium; qRT-PCR and immunoblotting; cell contraction/adhesion assays; gene microarray after HoxA13 manipulation","journal":"The Journal of clinical endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assays in primary human cells, transcriptional regulation demonstrated, single lab","pmids":["26485220"],"is_preprint":false},{"year":2016,"finding":"HoxA13 stimulates myometrial cells to secrete IL-1β, which in turn upregulates IL-6, IL-8, Cox-2 (cyclooxygenase-2), and connexin-43; blocking IL-1β abolishes HoxA13-mediated upregulation of these targets; HoxA13-induced IL-1β promotes recruitment of activated THP-1 monocytes via a mutual feed-forward loop that amplifies cytokine and contraction-associated protein expression.","method":"Gene microarray of HoxA13 transcriptome in myometrial cells; IL-1β inhibitor blockade experiment; co-culture of myometrial cells with THP-1 monocytes; qRT-PCR and protein assays","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptome profiling plus pharmacological inhibition rescue experiment, single lab","pmids":["26982635"],"is_preprint":false},{"year":2017,"finding":"HOXA13 directly binds the CDH17 promoter via HOXA13-binding sites (confirmed by dual luciferase assay); CDH17 is a downstream transcriptional target of HOXA13 that modulates the Wnt/β-catenin signaling pathway; CDH17 knockdown abrogates HOXA13-induced β-catenin upregulation in gastric cancer cells.","method":"Dual luciferase reporter assay; western blotting; siRNA knockdown; CCK-8/transwell assays","journal":"European review for medical and pharmacological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase assay confirming direct promoter binding plus epistasis via double knockdown, single lab","pmids":["28387908"],"is_preprint":false},{"year":2017,"finding":"HOXA13 promotes gastric cancer progression partly via activation of Erk1/2; RNA-Seq transcriptome analysis identified Erk1/2 pathway as the main downstream mechanism of HOXA13-induced proliferation and metastasis in gastric cancer cells.","method":"RNA-Seq transcriptome analysis; western blot; in vitro gain- and loss-of-function; xenograft/metastasis assays","journal":"OncoTargets and therapy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — RNA-Seq-based pathway inference without direct mechanistic demonstration of HOXA13 binding to Erk1/2 pathway components, single lab","pmids":["30881033"],"is_preprint":false},{"year":2021,"finding":"HOXA13 facilitates colorectal cancer metastasis by transactivating ACLY and IGF1R as direct downstream targets; knockdown of ACLY and IGF1R inhibits HOXA13-mediated metastasis; IGF1 upregulates HOXA13 expression through the PI3K/AKT/HIF1α pathway, forming a positive feedback loop (IGF1-HOXA13-IGF1R).","method":"Gain- and loss-of-function in CRC cells; rescue experiments with ACLY/IGF1R knockdown/overexpression; pathway inhibitor experiments; in vivo xenograft","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistatic rescue experiments with double knockdown/overexpression; pathway placement supported by pharmacological inhibitors; single lab","pmids":["34075028"],"is_preprint":false},{"year":2018,"finding":"HOXA13 directly binds the FN1 promoter region to enhance FAK/Src axis activation in gastric cancer, promoting proliferation and metastasis; this was confirmed by ChIP assay and dual luciferase reporter assay; HOXA13 is directly targeted by miR-449a (confirmed by luciferase assay); ITGA5 and ITGB1 interact with FN1 (confirmed by Co-immunoprecipitation).","method":"ChIP assay; dual luciferase reporter assay; Co-immunoprecipitation; in vitro and in vivo rescue experiments","journal":"Experimental hematology & oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding confirmed by ChIP and luciferase, FAK/Src pathway activation demonstrated biochemically, single lab","pmids":["35197128"],"is_preprint":false},{"year":2020,"finding":"Hoxa13 directly modulates Gli3 transcriptional regulation in developing limbs; in Hoxa13 mutants, Hoxd13 expression is lost from the presumptive digit 1 territory, resulting in increased Gli3 repressor activity due to elevated Gli3 transcription; Hox13 paralogs normally bind Gli3 regulatory sequences to suppress Gli3 transcription, thereby enabling 5'Hoxd gene expression and digit 1 formation.","method":"Hoxa13 mutant mouse analysis; ChIP-like regulatory element analysis; in situ hybridization; protein expression analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in vivo between Hoxa13 and Gli3/Hoxd13, regulatory binding demonstrated, single lab","pmids":["31896583"],"is_preprint":false},{"year":2017,"finding":"A prostate cancer risk element at 7p15.2 has long-range chromatin interactions with the HOXA locus (confirmed by Hi-C); CRISPR/Cas9 deletion of this element reveals it specifically represses HOXA13 and HOTTIP expression (but not other HOXA genes), via a repressive chromatin loop; HOXA13 forced expression was used to characterize downstream effects.","method":"Hi-C analysis; CRISPR/Cas9 deletion; RNA-seq","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Hi-C plus CRISPR deletion with transcriptomic readout, identifies specific regulatory element for HOXA13, single lab","pmids":["29117547"],"is_preprint":false},{"year":2019,"finding":"Hoxa13 plays a critical role in Müllerian duct fusion and in ureter remodeling by regulating elimination of the caudal common nephric duct; Hoxa13 function in the urogenital sinus is partly mediated by Gata3; Hoxa13 is required for proper organization of the ureter and provides positional and temporal cues in the lower urogenital system.","method":"Conditional inactivation strategy (Hoxa13 tissue-specific knockout); histological and molecular analysis of urogenital development","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional knockout with defined cellular phenotypes and molecular target (Gata3), single lab","pmids":["30649340"],"is_preprint":false},{"year":2019,"finding":"ChIP-Seq in developing mouse limbs identifies common target genes of HOXA11 and HOXA13; HOXA13-bound regions contain evolutionarily conserved sequences and multiple HOX binding sites; deletion of target regions neighboring Bmp2 or Tshz2 reduces their expression in the autopod confirming limb-specific enhancer function; HOXA13 transiently suspends cartilage differentiation in the autopod via repression of cartilage-promoting transcription factors (Aff3, Bnc2, Nfib, Runx1t1) and upregulation of Bcl11a.","method":"ChIP-Seq; Genechip transcriptome analysis of Hoxa13 KO and Hox13 double KO autopods; in situ hybridization; deletion of enhancer regions","journal":"Development, growth & differentiation","confidence":"High","confidence_rationale":"Tier 1 / Strong — ChIP-Seq plus loss-of-function transcriptomics plus in vivo enhancer deletion, multiple orthogonal methods","pmids":["30895612"],"is_preprint":false},{"year":2014,"finding":"NUP98-HOXA13 fusion protein (arising from chromosomal translocation t(7;11)(p15;p15)) binds the MSI2 promoter and deregulates MSI2 gene expression in blast crisis CML, as confirmed by chromatin immunoprecipitation.","method":"Chromatin immunoprecipitation; RT-PCR; cytogenetics","journal":"Molecular cytogenetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP directly confirming NUP98/HOXA13 fusion protein binding to MSI2 promoter; single case/lab","pmids":["24971156"],"is_preprint":false},{"year":2018,"finding":"HOXA13 directly binds the DHRS2 promoter in gastric cancer cells to down-regulate DHRS2 expression, thereby increasing MDM2 levels; HOXA13 also confers 5-FU resistance through MRP1 via a p53-dependent pathway.","method":"ChIP and reporter assays (inferred from description of 'directly down-regulating DHRS2'); in vitro and in vivo functional assays; western blot","journal":"Molecular carcinogenesis","confidence":"Low","confidence_rationale":"Tier 3 / Weak — direct regulation of DHRS2 stated but mechanistic demonstration methods not fully detailed in abstract; single lab","pmids":["29436749"],"is_preprint":false},{"year":2019,"finding":"Hoxa13 binds the FAM3A promoter to enhance its promoter activity in ischemic neuronal cells (HT22); overexpression of Hoxa13 inhibits chronic cerebral ischemia-induced neuronal apoptosis; the Snhg8/miR-384/Hoxa13/FAM3A axis regulates neuronal apoptosis, with miR-384 targeting the Hoxa13 3'UTR.","method":"Promoter-binding assay (luciferase); RNA immunoprecipitation; overexpression/knockdown in HT22 cells; in vivo mouse model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase promoter-binding assay plus in vivo confirmation, epistatic pathway dissection, single lab","pmids":["31165722"],"is_preprint":false},{"year":2022,"finding":"HOXA13 promotes liver regeneration by upregulating BMP-7 mRNA; overexpression of HOXA13 accelerates hepatocyte proliferation and liver function recovery in a mouse liver regeneration model.","method":"In vivo mouse liver regeneration model; HOXA13 overexpression in vivo and in vitro; gene expression analysis","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — upregulation of BMP-7 demonstrated but direct binding/transcriptional mechanism not validated in this study; single lab, single method","pmids":["35868069"],"is_preprint":false},{"year":2021,"finding":"HOXA13 upregulates ABCC4 expression to confer 5-FU resistance in gastric cancer; HOXA13 directly binds the ABCC4 promoter (confirmed by ChIP); HOXA13 is directly targeted by miR-139-5p (confirmed by luciferase reporter assay).","method":"ChIP assay; luciferase reporter assay; RNA-Seq; in vitro and in vivo functional assays","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus luciferase assay for direct binding, functional consequences demonstrated in vitro and in vivo, single lab","pmids":["34094932"],"is_preprint":false},{"year":2017,"finding":"A missense mutation in the HOXA13 homeodomain (V375F) impairs the ability of HOXA13 to activate transcription of the EPHA7 promoter, as demonstrated by luciferase reporter assay in a Chinese HFGS family.","method":"Sanger sequencing; luciferase reporter assay; molecular modelling","journal":"Journal of genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct transcriptional assay demonstrating functional impairment of specific missense mutation, consistent with known homeodomain function","pmids":["28947713"],"is_preprint":false}],"current_model":"HOXA13 is a homeodomain transcription factor that binds AT-rich DNA sequences (high-affinity consensus defined by SELEX and NMR structure) as a dimer, directly activating or repressing target genes—including Bmp2, Bmp7, EphA7, EphA6, Tie2, Foxf1, Aldh1a2, Sostdc1 (repressed), FN1, ABCC4, CDH17, and Gli3—to coordinate autopodal/digit patterning, urogenital tract morphogenesis, placental vascular specification, and myometrial regionalization; protein-protein interaction with MEIS family members provides additional regulatory specificity, and pathogenic mutations (nonsense, missense in the recognition helix, or polyalanine expansions causing protein aggregation and degradation) all cause the hand-foot-genital syndrome phenotype through loss of DNA-binding and transcriptional activity."},"narrative":{"mechanistic_narrative":"HOXA13 is a homeodomain transcription factor that patterns the distal limb (autopod), urogenital tract, and placental vasculature by binding AT-rich DNA and directly regulating target genes that govern cell adhesion, chondrogenesis, and signaling [PMID:8898214, PMID:9428414, PMID:17200107]. Its homeodomain recognizes a high-affinity AT-rich consensus and binds DNA as a dimer, with N-terminal arm minor-groove contacts and helix-3 major-groove recognition of an ATAA core; dimer-interface and recognition-helix residues are required for DNA binding and transcriptional activation [PMID:17200107, PMID:21829694]. Through these promoter and enhancer interactions HOXA13 activates Bmp2 and Bmp7 in the autopod, activates EphA7/EphA6 to control mesenchymal cell adhesion and chondrogenic condensation, activates Aldh1a2 to drive retinoic-acid-dependent interdigital cell death, and represses the BMP antagonist Sostdc1 to license BMP/SMAD signaling in the distal limb [PMID:11684655, PMID:15342482, PMID:16314414, PMID:17200107, PMID:17304517, PMID:23553814]. HOXA13 acts partially redundantly with Hoxd13 in autopod and posterior trunk morphogenesis and suppresses Gli3 transcription to enable digit 1 formation [PMID:8898214, PMID:9428414, PMID:31896583]. In urogenital development it sustains Fgf8 and Bmp7 in the urethral plate and directs Müllerian duct and ureter remodeling in part through Gata3, while in the placenta it activates Tie2 and Foxf1 to specify labyrinth vasculature [PMID:12783783, PMID:18483557, PMID:30649340]. Regulatory specificity is augmented by direct protein interaction with all MEIS family members through the C-terminal domain of MEIS1B [PMID:15617687]. Loss-of-function and dominant-negative HOXA13 mutations cause hand-foot-genital syndrome: nonsense and recognition-helix missense mutations abolish DNA binding and transactivation, while N-terminal polyalanine expansions reduce steady-state protein through enhanced degradation and form cytoplasmic aggregates that sequester wild-type HOXA13 and HOXD13 [PMID:9020844, PMID:10839976, PMID:15385446, PMID:17935235, PMID:28947713]. A recognition-helix missense allele combined with a promoter deletion underlies Guttmacher syndrome [PMID:11968094].","teleology":[{"year":1996,"claim":"Established that HOXA13 is genetically required for distal limb (autopod) skeletal patterning and acts partially redundantly with Hoxd13.","evidence":"Targeted Hoxa13 and Hoxd13 knockouts in mice with all allele combinations analyzed","pmids":["8898214"],"confidence":"High","gaps":["Did not identify direct molecular targets","Mechanism of redundancy with Hoxd13 unresolved"]},{"year":1995,"claim":"Showed HOXA13 confers a distal positional identity and controls homophilic cell-adhesive properties, linking a transcription factor to mesenchymal cell sorting.","evidence":"Retroviral misexpression in chick limb bud plus in vitro cell dissociation/reassociation assays","pmids":["7590231"],"confidence":"High","gaps":["Adhesion molecules mediating sorting not identified","Direct transcriptional targets unknown"]},{"year":1997,"claim":"Connected HOXA13 loss-of-function mutation to a human Mendelian disease and to urogenital/vascular morphogenesis, defining the homeodomain as the critical functional element.","evidence":"HFGS family sequencing identifying a homeodomain-truncating nonsense mutation; Hoxa13 knockout urogenital/umbilical artery phenotyping","pmids":["9020844","9428414"],"confidence":"High","gaps":["Biochemical demonstration of lost DNA binding not shown","Downstream targets in urogenital tract unidentified at this stage"]},{"year":2000,"claim":"Defined the spectrum and distinct mechanisms of HFGS-causing mutations (nonsense, polyalanine expansion, recognition-helix missense), revealing that mutation class shapes phenotype severity.","evidence":"Sequencing of multiple HFGS families with genotype-phenotype correlation; comparative vertebrate sequence analysis of the N-terminal polyalanine region; Hypodactyly frameshift protein characterization","pmids":["10839976","10656931","10625554"],"confidence":"Medium","gaps":["Functional mechanism of missense allele inferred not demonstrated","How polyalanine expansion impairs function not yet resolved"]},{"year":2001,"claim":"Identified the first direct effector pathway: HOXA13 regulates EphA7 to drive chondrogenic condensation, and established dominant Hoxa13 identity in limb and uterus via homeobox swap.","evidence":"Reciprocal genetics with EphA7 antibody-blocking in micromass culture; Hoxa11-to-Hoxa13 homeobox knock-in with expression profiling","pmids":["11684655","11688568"],"confidence":"High","gaps":["Direct HOXA13 binding to EphA7 not yet shown at this stage","Most of the >100 candidate targets uncharacterized"]},{"year":2002,"claim":"Demonstrated that specific HFGS mutant proteins can act as dominant negatives in vivo and linked a recognition-helix missense allele to Guttmacher syndrome.","evidence":"Retroviral overexpression of HFGa13 in chick caudal endoderm; allele dissection in a Guttmacher syndrome family","pmids":["11830557","11968094"],"confidence":"Medium","gaps":["Dominant-negative mechanism inferred from phenotype, not biochemistry","Promoter deletion contribution to Guttmacher phenotype unclear"]},{"year":2003,"claim":"Placed HOXA13 upstream of Fgf8/Bmp7 signaling in genital tubercle morphogenesis and showed it represses MyoD in limb muscle precursors.","evidence":"Hoxa13(GFP) mutant analysis with in vitro Fgf8 supplementation rescue; gain- and loss-of-function MyoD readout in chick and C2C12","pmids":["12783783","14706073"],"confidence":"Medium","gaps":["Direct binding to Fgf8/Bmp7 or MyoD regulatory regions not shown","Relationship between muscle and skeletal roles unclear"]},{"year":2004,"claim":"Provided the first direct in vivo evidence that HOXA13 binds and activates BMP gene enhancers, and that polyalanine expansion causes loss of function via protein destabilization.","evidence":"Enhancer-binding assays and ChIP from autopod with BMP2/BMP7 rescue; polyalanine-expansion knock-in mouse dissecting RNA vs protein vs translation","pmids":["15342482","15385446"],"confidence":"High","gaps":["Degradation machinery for expanded protein not identified","Quantitative contribution of BMP targets to full phenotype incomplete"]},{"year":2005,"claim":"Established the biochemical basis of HOXA13 specificity: direct EphA7 promoter regulation, MEIS cofactor interaction, and preference for AT-rich chromatin.","evidence":"ChIP and transactivation with binding-site mutagenesis on EphA7; yeast two-hybrid and Co-IP MEIS interaction mapping; CsCl-purified chromatin ChIP with AT-content analysis","pmids":["16314414","15617687","16321965"],"confidence":"High","gaps":["Functional consequence of MEIS interaction on target selection in vivo not resolved","Genome-wide binding landscape not yet mapped"]},{"year":2007,"claim":"Defined the high-affinity AT-rich binding consensus, added repression (Sostdc1) and vascular (EphA6/EphA7) targets, and linked polyalanine aggregates to sequestration of wild-type Hox proteins.","evidence":"SELEX binding-site determination with limb ChIP and reporter assays; genital tubercle ChIP for EphA6/EphA7; COS-cell aggregation and geldanamycin co-aggregation assays","pmids":["17200107","17304517","17935235"],"confidence":"High","gaps":["Determinants of activation versus repression at AT-rich sites unclear","Role of Hsp90 in vivo in HFGS not established"]},{"year":2008,"claim":"Extended HOXA13 direct transcriptional control to placental labyrinth vasculature via Tie2 and Foxf1, with quantified high-affinity promoter binding.","evidence":"Hoxa13 mutant placenta microarray, placental ChIP, in vitro affinity measurement (Kd 27-42 nM), and reporter assays","pmids":["18483557"],"confidence":"High","gaps":["Cofactor requirements for vascular target selection unknown","Whether placental and limb targets share regulatory logic untested"]},{"year":2011,"claim":"Provided atomic-level mechanism of DNA recognition, showing HOXA13 binds as a dimer with defined residues required for binding, dimerization, and transactivation.","evidence":"NMR structure of the homeodomain-DNA complex with site-directed mutagenesis and dual binding/transcription assays","pmids":["21829694"],"confidence":"High","gaps":["Structure of full-length protein with N-terminal region and cofactors absent","Generality of dimeric binding across all targets untested"]},{"year":2013,"claim":"Linked HOXA13 to retinoic-acid-driven interdigital programmed cell death through direct Aldh1a2 regulation.","evidence":"Limb ChIP and reporter assays plus maternal RA supplementation rescue in Hoxa13 mutants","pmids":["23553814"],"confidence":"High","gaps":["Interaction of RA pathway with BMP-dependent cell death not integrated","Partial rescue indicates additional unidentified targets"]},{"year":2019,"claim":"Mapped HOXA13 genome-wide binding in limb and revealed it transiently suspends cartilage differentiation by repressing pro-chondrogenic factors while validating enhancers near Bmp2 and Tshz2.","evidence":"ChIP-Seq with KO and double-KO transcriptomics and in vivo enhancer deletions; conditional KO defining Müllerian/ureter roles via Gata3","pmids":["30895612","30649340"],"confidence":"High","gaps":["Direct versus indirect status of many repressed factors unresolved","Temporal control of the differentiation switch mechanism incomplete"]},{"year":2020,"claim":"Integrated HOXA13 into the digit-1 patterning network by showing it suppresses Gli3 transcription to permit 5'Hoxd expression.","evidence":"Hoxa13 mutant analysis with regulatory-element binding and in situ hybridization epistasis","pmids":["31896583"],"confidence":"Medium","gaps":["Direct binding to Gli3 regulatory sequences shown indirectly","Interplay with Hoxd13 at this locus not fully dissected"]},{"year":2021,"claim":"Documented HOXA13 as an oncogenic transcription factor in epithelial cancers, directly activating target genes that drive proliferation, metastasis, and chemoresistance.","evidence":"ChIP/luciferase identification of CDH17, FN1, ABCC4 as direct targets; epistatic rescue with ACLY/IGF1R; miRNA-mediated regulation of HOXA13","pmids":["28387908","35197128","34094932","34075028"],"confidence":"Medium","gaps":["Cofactor and chromatin context for cancer targets versus developmental targets unclear","Most cancer findings from single labs without independent replication"]},{"year":2017,"claim":"Showed that HOXA13 expression itself is controlled by a long-range repressive chromatin element at the HOXA locus, and that an oncogenic NUP98-HOXA13 fusion deregulates MSI2.","evidence":"Hi-C and CRISPR deletion of a 7p15.2 element with RNA-seq; ChIP of NUP98-HOXA13 fusion on the MSI2 promoter","pmids":["29117547","24971156"],"confidence":"Medium","gaps":["Mechanism of repressive loop formation undefined","NUP98-HOXA13 target repertoire beyond MSI2 unknown"]},{"year":null,"claim":"How HOXA13 selects activation versus repression at AT-rich sites, and how MEIS and chromatin context route the same DNA-binding activity to distinct developmental versus oncogenic gene programs, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of HOXA13-MEIS-DNA ternary complex","Determinants distinguishing developmental from cancer target selection unknown","Mechanism of polyalanine-driven degradation not molecularly defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[6,12,15,16,18,20,35]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[14,15,18,19]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[17,22]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[17]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[6,12,15,18]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,2,3,4,35]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,15,20]}],"complexes":[],"partners":["MEIS1","MEIS2","MEIS3","HOXD13"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P31271","full_name":"Homeobox protein Hox-A13","aliases":["Homeobox protein Hox-1J"],"length_aa":388,"mass_kda":39.7,"function":"Sequence-specific, AT-rich binding transcription factor which is part of a developmental regulatory system that provides cells with specific positional identities on the anterior-posterior axis Sequence-specific transcription factor which is part of a developmental regulatory system that provides cells with specific positional identities on the anterior-posterior axis","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P31271/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HOXA13","classification":"Not Classified","n_dependent_lines":16,"n_total_lines":1208,"dependency_fraction":0.013245033112582781},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PARP1","stoichiometry":0.2},{"gene":"PSME4","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/HOXA13","total_profiled":1310},"omim":[{"mim_id":"620706","title":"DEVELOPING BRAIN HOMEOBOX 2; DBX2","url":"https://www.omim.org/entry/620706"},{"mim_id":"614060","title":"HOXA DISTAL TRANSCRIPT ANTISENSE RNA; HOTTIP","url":"https://www.omim.org/entry/614060"},{"mim_id":"610713","title":"BRACHYDACTYLY-SYNDACTYLY SYNDROME; BDSD","url":"https://www.omim.org/entry/610713"},{"mim_id":"609296","title":"B-CELL IMMUNODEFICIENCY, DISTAL LIMB ANOMALIES, AND UROGENITAL MALFORMATIONS; BILU","url":"https://www.omim.org/entry/609296"},{"mim_id":"606708","title":"SPLIT-HAND/FOOT MALFORMATION 5; SHFM5","url":"https://www.omim.org/entry/606708"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Mitotic chromosome","reliability":"Additional"},{"location":"Intermediate filaments","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"cervix","ntpm":21.0},{"tissue":"placenta","ntpm":16.0},{"tissue":"prostate","ntpm":20.9},{"tissue":"seminal 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functional inference from homeodomain truncation\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct identification of loss-of-function mutation affecting the DNA-binding homeodomain, replicated across multiple families in subsequent studies\",\n      \"pmids\": [\"9020844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Hoxa13 gene knockout in mice causes loss of the most anterior digit and altered morphogenesis of preaxial carpal/tarsal elements in both forelimb and hindlimb autopods; Hoxa13 and Hoxd13 act in a partially redundant manner, and double homozygous mutants almost completely lack chondrified condensations in the autopod.\",\n      \"method\": \"Targeted gene disruption (knockout), analysis of all allele combinations of Hoxa13 and Hoxd13\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic knockouts with defined skeletal phenotype, all allele combinations tested, replicated by multiple subsequent studies\",\n      \"pmids\": [\"8898214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Hoxa13 homozygous knockout mice display agenesis of the caudal portion of Müllerian ducts, absence of presumptive urinary bladder development, and premature stenosis of umbilical arteries, leading to mid-gestational lethality; Hoxa13 and Hoxd13 act redundantly in early morphogenesis of posterior trunk structures including the cloaca.\",\n      \"method\": \"Targeted gene disruption (knockout); histological and morphological analysis of compound mutants\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic knockouts with multiple defined urogenital/digestive phenotypes, all allele combinations analyzed\",\n      \"pmids\": [\"9428414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Misexpression of Hoxa-13 throughout the chick limb bud caused homeotic transformation of zeugopodal cartilages to a more distal (carpal/tarsal) fate and altered homophilic cell-adhesive properties of limb mesenchymal cells, causing Hoxa13-expressing cells to sort out from non-expressing cells in dissociation culture.\",\n      \"method\": \"Replication-competent retroviral misexpression in chick limb buds; in vitro cell dissociation and reassociation assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gain-of-function misexpression combined with in vitro cell adhesion assays with defined phenotypic readouts\",\n      \"pmids\": [\"7590231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"In Hoxa13 mutant mice, EphA7 expression is markedly reduced in affected digits and in mutant mesenchymal micromass cultures; antibody blocking of EphA7 extracellular domain severely inhibits chondrogenic condensation of Hoxa13-expressing heterozygous cells in vitro, indicating that Hoxa13 regulates EphA7 to control mesenchymal cell adhesion and chondrogenic condensation.\",\n      \"method\": \"FACS isolation of GFP-tagged Hoxa13 mutant mesenchymal cells; in vitro micromass chondrogenic assay; antibody blocking experiments; in situ hybridization\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal loss-of-function genetics plus functional antibody blocking with defined cellular phenotype\",\n      \"pmids\": [\"11684655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Hoxa13 is required for normal expression of Fgf8 and Bmp7 in the urethral plate epithelium; loss of Hoxa13 causes hypospadias through combined loss of Fgf8 and Bmp7 expression and ectopic noggin expression; Fgf8 supplementation restores proliferation to wild-type levels in mutant genital tubercle, and reduced Bmp7 explains closure defects through loss of apoptosis; Hoxa13 mutants also show altered androgen receptor expression.\",\n      \"method\": \"Hoxa13(GFP) mutant mouse analysis; in vitro Fgf8 supplementation rescue assay; in situ hybridization; immunohistochemistry\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function with rescue experiment, multiple orthogonal methods including supplementation assay\",\n      \"pmids\": [\"12783783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"HOXA13 directly binds novel enhancer regions of Bmp2 and Bmp7 to activate their expression in the developing autopod; endogenous HOXA13-Bmp2 and HOXA13-Bmp7 enhancer complexes were confirmed by immunoprecipitation from autopod tissue; exogenous BMP2 or BMP7 application partially rescues the Hoxa13 mutant limb phenotype.\",\n      \"method\": \"Biochemical enhancer-binding assays; chromatin immunoprecipitation from developing autopod; exogenous BMP2/BMP7 rescue of mutant limb phenotype\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro DNA binding assays, ChIP from tissue, and in vivo rescue experiment; multiple orthogonal methods\",\n      \"pmids\": [\"15342482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Replacement of the Hoxa11 homeobox with the Hoxa13 homeobox (knock-in) confers dominant Hoxa13 function in the limbs and female reproductive tract, causing homeotic transformation of the uterus towards a cervix/vagina identity; gene chip analysis identified over 100 downstream gene expression changes consistent with Hoxa13 target genes.\",\n      \"method\": \"Homeobox-swap knock-in mouse; gene expression profiling (gene chips); histological analysis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo homeobox swap with defined homeotic transformation phenotype plus genome-wide target gene identification\",\n      \"pmids\": [\"11688568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Polyalanine expansions in the N-terminal region of HOXA13 cause hand-foot-genital syndrome; N-terminal sequence is strongly conserved among vertebrates and harbors multiple conserved domains shared with Drosophila AbdB; three large alanine repeats arose after divergence of reptiles from the mammalian lineage, possibly by replication slippage.\",\n      \"method\": \"PCR amplification and sequencing of HOXA13 N-terminal coding sequences across vertebrate species; comparative sequence analysis\",\n      \"journal\": \"Mammalian genome\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — comparative sequencing revealing evolutionary conservation, single method but broad taxonomic sampling\",\n      \"pmids\": [\"10656931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Novel HOXA13 mutations causing HFGS include nonsense mutations (N-terminal to or within homeodomain), a polyalanine expansion, and a missense mutation at an invariant homeodomain residue; the missense mutation produces an exceptionally severe limb phenotype, indicating that different mutation types can act by distinct mechanisms (loss of function vs. potentially altered function).\",\n      \"method\": \"Mutation identification by sequencing in six HFGS families; clinical phenotype correlation\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple independent families with different mutation classes, phenotype-genotype correlation, but functional mechanism of missense inferred rather than directly demonstrated\",\n      \"pmids\": [\"10839976\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"A specific HOXA13 mutation (HFGa13) acts as a dominant negative in vivo; overexpression of HFGa13 in chick caudal endoderm causes taillessness and severe gut/genitourinary malformations; HFGa13 negatively regulates Hoxd13 expression and antagonizes functions of endogenous Hoxa13 and Hoxd13.\",\n      \"method\": \"Retroviral overexpression in chick caudal endoderm; in situ hybridization; phenotypic analysis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function in vivo experiment with defined phenotype, but dominant-negative mechanism inferred from phenotypic comparison rather than direct biochemical demonstration\",\n      \"pmids\": [\"11830557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Polyalanine expansion mutations in HOXA13 (tested in mouse knock-in model, +10 alanines in third polyalanine tract) cause loss of function through reduction of steady-state protein levels in vivo, not through impaired mRNA expression or splicing; in vitro translation efficiency is normal, implicating enhanced protein degradation as the mechanism.\",\n      \"method\": \"Homologous recombination knock-in mouse; quantitative RT-PCR; western blot; in vitro translation assay\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knock-in mouse model with mechanistic dissection using multiple orthogonal assays (RNA vs protein vs translation)\",\n      \"pmids\": [\"15385446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"HOXA13 and HOXD13 directly bind multiple conserved sites in the EphA7 promoter in vivo and in vitro, and activate EphA7 transcription; a mutation of the HOXA13/HOXD13 binding site in the EphA7 promoter abolishes transcriptional activation; the HOXD13(147L) brachydactyly-polydactyly mutation fails to bind the EphA7 promoter or transactivate it.\",\n      \"method\": \"Promoter characterization; in vivo ChIP in developing mouse limbs; in vitro transcription activation assays; mutagenesis of binding site\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — promoter binding confirmed by ChIP in vivo plus in vitro transactivation with mutagenesis, replicated across multiple Hox group 13 proteins\",\n      \"pmids\": [\"16314414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"HOXA13 interacts with all MEIS proteins (MEIS1A, MEIS1B, MEIS2, MEIS3) but not more diverged TALE superclass members; the C-terminal domain of MEIS1B (93 amino acids) is both necessary and sufficient for HOXA13 interaction; multiple HOX peptide domains contribute to MEIS binding; HOXA13 and MEIS1 coexpression occurs in developing male and female reproductive tracts.\",\n      \"method\": \"Yeast two-hybrid assays; Co-immunoprecipitation in mammalian cells; deletion mutagenesis of MEIS domains; expression analysis\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP in mammalian cells plus yeast two-hybrid with systematic deletion analysis\",\n      \"pmids\": [\"15617687\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"HOXA13 binds AT-rich chromatin immunoprecipitated fragments (Hox-enriched fragments, HEFs) in NIH 3T3 cells; all HEFs augment transcription of a heterologous promoter when HOXA13 is coexpressed; multiple HOXA13 binding sites in the Enpp2 locus are necessary for full HOXA13-induced Enpp2 expression; HOXA13 upregulates Enpp2 without changing general histone acetylation at its locus.\",\n      \"method\": \"CsCl centrifugation-based chromatin purification and immunoprecipitation (ChIP); transcriptional reporter assays; AT-content analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with transcriptional validation and site mutagenesis, single lab\",\n      \"pmids\": [\"16321965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"HOXA13 homeodomain binds DNA with a novel high-affinity site (AT-rich); HOXA13 binds and represses the BMP antagonist Sostdc1 through two conserved regulatory sites in vivo (confirmed by limb ChIP); absence of HOXA13 leads to ectopic Sostdc1 expression, reduced BMP-activated gene expression, and decreased SMAD phosphorylation in the distal limb.\",\n      \"method\": \"Empirical SELEX-based DNA binding site determination; limb ChIP; in vitro reporter assays; analysis of Hoxa13 mutant limbs\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — DNA binding site empirically determined, ChIP in vivo, reporter assays with dosage dependence, confirmed in Hoxa13 mutant tissue\",\n      \"pmids\": [\"17200107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"HOXA13 directly regulates EphA6 and EphA7 expression in the genital tubercle (GT) vascular endothelia; HOXA13 binds conserved cis-regulatory elements in the EphA6 and EphA7 promoters with high affinity; GT ChIP confirms HOXA13 binding in vivo; HOXA13 activates EphA6 and EphA7 expression through these regulatory elements in vitro; loss of HOXA13 is associated with reduced EphA6/EphA7 and vascular defects in the GT.\",\n      \"method\": \"In vitro DNA-binding assays; chromatin immunoprecipitation from genital tubercle; transcriptional reporter assays in vitro\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro binding, ChIP in vivo, reporter assays; loss-of-function phenotypic correlation\",\n      \"pmids\": [\"17304517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"HOXA13 polyalanine expansion proteins form cytoplasmic aggregates; distribution between cytoplasm and nucleus is polyalanine tract size-dependent; Hsp90 inhibitor geldanamycin reduces steady-state abundance of expanded HOXA13 proteins; wild-type HOXA13 and HOXD13 are sequestered in polyalanine expansion aggregates, explaining dominant-negative effects.\",\n      \"method\": \"COS cell transfection with polyalanine-expanded HOXA13 constructs; immunocytochemistry; geldanamycin treatment; co-aggregation assays\",\n      \"journal\": \"American journal of medical genetics. Part A\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — cellular imaging of aggregation with pharmacological manipulation, co-aggregation demonstrated, single lab\",\n      \"pmids\": [\"17935235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"HOXA13 is essential for placental labyrinth vascular formation; loss of HOXA13 alters placental endothelial cell morphology and reduces expression of Tie2 and Foxf1; HOXA13 directly binds the Tie2 and Foxf1 promoters in vivo (placental ChIP) with high affinity (Kd = 27–42 nM); HOXA13 can use bound promoter regions to activate gene expression in vitro.\",\n      \"method\": \"Hoxa13 mutant mouse analysis; microarray; ChIP from placenta; in vitro DNA binding (affinity measurement); reporter assays\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — ChIP in vivo, in vitro binding quantification, reporter assays, loss-of-function with defined vascular phenotype\",\n      \"pmids\": [\"18483557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"NMR structure of the HOXA13 homeodomain (A13DBD) bound to an 11-mer DNA duplex reveals: the protein forms a dimer binding DNA with Kd of 7.5 nM; the N-terminal arm contacts the minor groove; helix 3 contacts the ATAA sequence in the major groove; N370 forms hydrogen bonds with adenine; V373 methyl groups contact T5, T6*, T7* for TAA recognition; I366 contacts T3* and T4*; R337, K343, F344 form the dimer interface. Mutants I366A, N370A, V373G reduce DNA binding and transcriptional activity; F344A weakens dimerization and reduces transcriptional activity by 76%.\",\n      \"method\": \"NMR structure determination; site-directed mutagenesis; DNA binding assays; transcriptional activity assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structure with functional validation by mutagenesis across multiple sites and two orthogonal functional assays\",\n      \"pmids\": [\"21829694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"HOXA13 directly regulates Aldh1a2 (the primary retinoic acid synthesizing enzyme in the limb) by binding a conserved cis-regulatory element in the Aldh1a2 locus; loss of HOXA13 reduces Aldh1a2 expression, RA signaling, and interdigital programmed cell death (IPCD); maternal RA supplementation partially rescues IPCD defects in Hoxa13 mutant hindlimbs.\",\n      \"method\": \"ChIP from limb tissue; reporter assays; RA signaling readout; maternal RA supplementation rescue in Hoxa13 mutants\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — ChIP plus reporter assay plus in vivo rescue experiment, multiple orthogonal validations\",\n      \"pmids\": [\"23553814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Guttmacher syndrome is caused by a HOXA13 missense mutation in the recognition helix of the homeodomain (Q50L) combined with a 2-bp promoter deletion; the promoter deletion alone produces no detectable phenotype; the missense mutation is predicted to perturb DNA-binding properties, potentially resulting in both loss and specific gain of function.\",\n      \"method\": \"Sequencing of HOXA13 in Guttmacher syndrome family; molecular analysis of promoter deletion in isolation\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct mutation identification with functional inference; mechanistic distinction from pure loss-of-function established by genetic dissection of alleles\",\n      \"pmids\": [\"11968094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The Hypodactyly (Hoxa13Hd) 50-bp deletion causes a translational frameshift producing a novel stable protein (HOXA13Hd) consisting of the first 25 wild-type amino acids plus 275 arginine/lysine-rich novel residues, lacking the homeodomain; HOXA13Hd localizes to the nucleus in transfected COS-7 cells; transgenic misexpression of HOXA13Hd in developing limbs produces severe proximal and distal limb reduction defects.\",\n      \"method\": \"Transcription start site mapping; immunoprecipitation; cell transfection with immunolocalization; transgenic misexpression in mouse limb\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — protein characterization, subcellular localization, in vivo transgenic gain-of-function with defined phenotype\",\n      \"pmids\": [\"10625554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Hoxa-13 and Hoxa-11 are expressed in limb muscle precursor cells and represses MyoD expression; forced expression of Hoxa-13 in limb muscle precursors or C2C12 myoblasts causes pronounced repression of MyoD; targeted disruption of Hoxa-13 results in enhanced MyoD expression in the flexor carpi radialis muscle, confirming endogenous regulation.\",\n      \"method\": \"In ovo electroporation; C2C12 cell transfection; gene knockout with in situ hybridization\",\n      \"journal\": \"Development, growth & differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with defined molecular readout (MyoD expression), replicated across two experimental systems\",\n      \"pmids\": [\"14706073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Surviving Hoxa13 homozygous mutant mice display missing phalanges, fused carpal/tarsal elements, and reduced metacarpal/metatarsal length; Gdf5 expression is significantly reduced and diffuse in affected carpal/tarsal anlagen, identifying Gdf5 as a potential direct HOXA13 target gene involved in skeletal element delineation; Bmp2 expression is elevated.\",\n      \"method\": \"Analysis of surviving Hoxa13(GFP) homozygous mutants; quantitative gene expression analysis; in situ hybridization\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic loss-of-function with defined molecular phenotype, but Gdf5 described as 'potential' target without direct binding confirmation\",\n      \"pmids\": [\"20034107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"HOXA13 directly regulates expression of Fgf8 and Bmp7 in the urethral plate, and is also required for the development of the glans penis vasculature; HOXA13 regulates genes required for proper androgen signaling in the genital tubercle.\",\n      \"method\": \"Hoxa13 mutant mouse; expression analysis of downstream targets; in vitro proliferation rescue with Fgf8\",\n      \"journal\": \"Genesis (New York, N.Y. : 2000)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with defined target gene changes, corroborated by functional rescue; localization data from Cre-fate mapping\",\n      \"pmids\": [\"25980463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"HoxA13 is more highly expressed in the lower uterine segment (LUS) than the fundal myometrium during pregnancy; HoxA13 upregulates transcription of PTGIS and POSTN in myometrial cells; elevated HoxA13 enhances myometrial cell contractility and cell-cell adhesion; HoxA13-regulated genes are associated with immune response, gap junction/cell adhesion, and pregnancy.\",\n      \"method\": \"RNA sequencing of human myometrium; qRT-PCR and immunoblotting; cell contraction/adhesion assays; gene microarray after HoxA13 manipulation\",\n      \"journal\": \"The Journal of clinical endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assays in primary human cells, transcriptional regulation demonstrated, single lab\",\n      \"pmids\": [\"26485220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"HoxA13 stimulates myometrial cells to secrete IL-1β, which in turn upregulates IL-6, IL-8, Cox-2 (cyclooxygenase-2), and connexin-43; blocking IL-1β abolishes HoxA13-mediated upregulation of these targets; HoxA13-induced IL-1β promotes recruitment of activated THP-1 monocytes via a mutual feed-forward loop that amplifies cytokine and contraction-associated protein expression.\",\n      \"method\": \"Gene microarray of HoxA13 transcriptome in myometrial cells; IL-1β inhibitor blockade experiment; co-culture of myometrial cells with THP-1 monocytes; qRT-PCR and protein assays\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptome profiling plus pharmacological inhibition rescue experiment, single lab\",\n      \"pmids\": [\"26982635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HOXA13 directly binds the CDH17 promoter via HOXA13-binding sites (confirmed by dual luciferase assay); CDH17 is a downstream transcriptional target of HOXA13 that modulates the Wnt/β-catenin signaling pathway; CDH17 knockdown abrogates HOXA13-induced β-catenin upregulation in gastric cancer cells.\",\n      \"method\": \"Dual luciferase reporter assay; western blotting; siRNA knockdown; CCK-8/transwell assays\",\n      \"journal\": \"European review for medical and pharmacological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase assay confirming direct promoter binding plus epistasis via double knockdown, single lab\",\n      \"pmids\": [\"28387908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HOXA13 promotes gastric cancer progression partly via activation of Erk1/2; RNA-Seq transcriptome analysis identified Erk1/2 pathway as the main downstream mechanism of HOXA13-induced proliferation and metastasis in gastric cancer cells.\",\n      \"method\": \"RNA-Seq transcriptome analysis; western blot; in vitro gain- and loss-of-function; xenograft/metastasis assays\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — RNA-Seq-based pathway inference without direct mechanistic demonstration of HOXA13 binding to Erk1/2 pathway components, single lab\",\n      \"pmids\": [\"30881033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HOXA13 facilitates colorectal cancer metastasis by transactivating ACLY and IGF1R as direct downstream targets; knockdown of ACLY and IGF1R inhibits HOXA13-mediated metastasis; IGF1 upregulates HOXA13 expression through the PI3K/AKT/HIF1α pathway, forming a positive feedback loop (IGF1-HOXA13-IGF1R).\",\n      \"method\": \"Gain- and loss-of-function in CRC cells; rescue experiments with ACLY/IGF1R knockdown/overexpression; pathway inhibitor experiments; in vivo xenograft\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistatic rescue experiments with double knockdown/overexpression; pathway placement supported by pharmacological inhibitors; single lab\",\n      \"pmids\": [\"34075028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HOXA13 directly binds the FN1 promoter region to enhance FAK/Src axis activation in gastric cancer, promoting proliferation and metastasis; this was confirmed by ChIP assay and dual luciferase reporter assay; HOXA13 is directly targeted by miR-449a (confirmed by luciferase assay); ITGA5 and ITGB1 interact with FN1 (confirmed by Co-immunoprecipitation).\",\n      \"method\": \"ChIP assay; dual luciferase reporter assay; Co-immunoprecipitation; in vitro and in vivo rescue experiments\",\n      \"journal\": \"Experimental hematology & oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding confirmed by ChIP and luciferase, FAK/Src pathway activation demonstrated biochemically, single lab\",\n      \"pmids\": [\"35197128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Hoxa13 directly modulates Gli3 transcriptional regulation in developing limbs; in Hoxa13 mutants, Hoxd13 expression is lost from the presumptive digit 1 territory, resulting in increased Gli3 repressor activity due to elevated Gli3 transcription; Hox13 paralogs normally bind Gli3 regulatory sequences to suppress Gli3 transcription, thereby enabling 5'Hoxd gene expression and digit 1 formation.\",\n      \"method\": \"Hoxa13 mutant mouse analysis; ChIP-like regulatory element analysis; in situ hybridization; protein expression analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in vivo between Hoxa13 and Gli3/Hoxd13, regulatory binding demonstrated, single lab\",\n      \"pmids\": [\"31896583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A prostate cancer risk element at 7p15.2 has long-range chromatin interactions with the HOXA locus (confirmed by Hi-C); CRISPR/Cas9 deletion of this element reveals it specifically represses HOXA13 and HOTTIP expression (but not other HOXA genes), via a repressive chromatin loop; HOXA13 forced expression was used to characterize downstream effects.\",\n      \"method\": \"Hi-C analysis; CRISPR/Cas9 deletion; RNA-seq\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Hi-C plus CRISPR deletion with transcriptomic readout, identifies specific regulatory element for HOXA13, single lab\",\n      \"pmids\": [\"29117547\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Hoxa13 plays a critical role in Müllerian duct fusion and in ureter remodeling by regulating elimination of the caudal common nephric duct; Hoxa13 function in the urogenital sinus is partly mediated by Gata3; Hoxa13 is required for proper organization of the ureter and provides positional and temporal cues in the lower urogenital system.\",\n      \"method\": \"Conditional inactivation strategy (Hoxa13 tissue-specific knockout); histological and molecular analysis of urogenital development\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional knockout with defined cellular phenotypes and molecular target (Gata3), single lab\",\n      \"pmids\": [\"30649340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ChIP-Seq in developing mouse limbs identifies common target genes of HOXA11 and HOXA13; HOXA13-bound regions contain evolutionarily conserved sequences and multiple HOX binding sites; deletion of target regions neighboring Bmp2 or Tshz2 reduces their expression in the autopod confirming limb-specific enhancer function; HOXA13 transiently suspends cartilage differentiation in the autopod via repression of cartilage-promoting transcription factors (Aff3, Bnc2, Nfib, Runx1t1) and upregulation of Bcl11a.\",\n      \"method\": \"ChIP-Seq; Genechip transcriptome analysis of Hoxa13 KO and Hox13 double KO autopods; in situ hybridization; deletion of enhancer regions\",\n      \"journal\": \"Development, growth & differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — ChIP-Seq plus loss-of-function transcriptomics plus in vivo enhancer deletion, multiple orthogonal methods\",\n      \"pmids\": [\"30895612\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NUP98-HOXA13 fusion protein (arising from chromosomal translocation t(7;11)(p15;p15)) binds the MSI2 promoter and deregulates MSI2 gene expression in blast crisis CML, as confirmed by chromatin immunoprecipitation.\",\n      \"method\": \"Chromatin immunoprecipitation; RT-PCR; cytogenetics\",\n      \"journal\": \"Molecular cytogenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP directly confirming NUP98/HOXA13 fusion protein binding to MSI2 promoter; single case/lab\",\n      \"pmids\": [\"24971156\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HOXA13 directly binds the DHRS2 promoter in gastric cancer cells to down-regulate DHRS2 expression, thereby increasing MDM2 levels; HOXA13 also confers 5-FU resistance through MRP1 via a p53-dependent pathway.\",\n      \"method\": \"ChIP and reporter assays (inferred from description of 'directly down-regulating DHRS2'); in vitro and in vivo functional assays; western blot\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — direct regulation of DHRS2 stated but mechanistic demonstration methods not fully detailed in abstract; single lab\",\n      \"pmids\": [\"29436749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Hoxa13 binds the FAM3A promoter to enhance its promoter activity in ischemic neuronal cells (HT22); overexpression of Hoxa13 inhibits chronic cerebral ischemia-induced neuronal apoptosis; the Snhg8/miR-384/Hoxa13/FAM3A axis regulates neuronal apoptosis, with miR-384 targeting the Hoxa13 3'UTR.\",\n      \"method\": \"Promoter-binding assay (luciferase); RNA immunoprecipitation; overexpression/knockdown in HT22 cells; in vivo mouse model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase promoter-binding assay plus in vivo confirmation, epistatic pathway dissection, single lab\",\n      \"pmids\": [\"31165722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HOXA13 promotes liver regeneration by upregulating BMP-7 mRNA; overexpression of HOXA13 accelerates hepatocyte proliferation and liver function recovery in a mouse liver regeneration model.\",\n      \"method\": \"In vivo mouse liver regeneration model; HOXA13 overexpression in vivo and in vitro; gene expression analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — upregulation of BMP-7 demonstrated but direct binding/transcriptional mechanism not validated in this study; single lab, single method\",\n      \"pmids\": [\"35868069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HOXA13 upregulates ABCC4 expression to confer 5-FU resistance in gastric cancer; HOXA13 directly binds the ABCC4 promoter (confirmed by ChIP); HOXA13 is directly targeted by miR-139-5p (confirmed by luciferase reporter assay).\",\n      \"method\": \"ChIP assay; luciferase reporter assay; RNA-Seq; in vitro and in vivo functional assays\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus luciferase assay for direct binding, functional consequences demonstrated in vitro and in vivo, single lab\",\n      \"pmids\": [\"34094932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A missense mutation in the HOXA13 homeodomain (V375F) impairs the ability of HOXA13 to activate transcription of the EPHA7 promoter, as demonstrated by luciferase reporter assay in a Chinese HFGS family.\",\n      \"method\": \"Sanger sequencing; luciferase reporter assay; molecular modelling\",\n      \"journal\": \"Journal of genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct transcriptional assay demonstrating functional impairment of specific missense mutation, consistent with known homeodomain function\",\n      \"pmids\": [\"28947713\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HOXA13 is a homeodomain transcription factor that binds AT-rich DNA sequences (high-affinity consensus defined by SELEX and NMR structure) as a dimer, directly activating or repressing target genes—including Bmp2, Bmp7, EphA7, EphA6, Tie2, Foxf1, Aldh1a2, Sostdc1 (repressed), FN1, ABCC4, CDH17, and Gli3—to coordinate autopodal/digit patterning, urogenital tract morphogenesis, placental vascular specification, and myometrial regionalization; protein-protein interaction with MEIS family members provides additional regulatory specificity, and pathogenic mutations (nonsense, missense in the recognition helix, or polyalanine expansions causing protein aggregation and degradation) all cause the hand-foot-genital syndrome phenotype through loss of DNA-binding and transcriptional activity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"HOXA13 is a homeodomain transcription factor that patterns the distal limb (autopod), urogenital tract, and placental vasculature by binding AT-rich DNA and directly regulating target genes that govern cell adhesion, chondrogenesis, and signaling [#1, #2, #15]. Its homeodomain recognizes a high-affinity AT-rich consensus and binds DNA as a dimer, with N-terminal arm minor-groove contacts and helix-3 major-groove recognition of an ATAA core; dimer-interface and recognition-helix residues are required for DNA binding and transcriptional activation [#15, #19]. Through these promoter and enhancer interactions HOXA13 activates Bmp2 and Bmp7 in the autopod, activates EphA7/EphA6 to control mesenchymal cell adhesion and chondrogenic condensation, activates Aldh1a2 to drive retinoic-acid-dependent interdigital cell death, and represses the BMP antagonist Sostdc1 to license BMP/SMAD signaling in the distal limb [#4, #6, #12, #15, #16, #20]. HOXA13 acts partially redundantly with Hoxd13 in autopod and posterior trunk morphogenesis and suppresses Gli3 transcription to enable digit 1 formation [#1, #2, #32]. In urogenital development it sustains Fgf8 and Bmp7 in the urethral plate and directs Müllerian duct and ureter remodeling in part through Gata3, while in the placenta it activates Tie2 and Foxf1 to specify labyrinth vasculature [#5, #18, #34]. Regulatory specificity is augmented by direct protein interaction with all MEIS family members through the C-terminal domain of MEIS1B [#13]. Loss-of-function and dominant-negative HOXA13 mutations cause hand-foot-genital syndrome: nonsense and recognition-helix missense mutations abolish DNA binding and transactivation, while N-terminal polyalanine expansions reduce steady-state protein through enhanced degradation and form cytoplasmic aggregates that sequester wild-type HOXA13 and HOXD13 [#0, #9, #11, #17, #41]. A recognition-helix missense allele combined with a promoter deletion underlies Guttmacher syndrome [#21].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established that HOXA13 is genetically required for distal limb (autopod) skeletal patterning and acts partially redundantly with Hoxd13.\",\n      \"evidence\": \"Targeted Hoxa13 and Hoxd13 knockouts in mice with all allele combinations analyzed\",\n      \"pmids\": [\"8898214\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify direct molecular targets\", \"Mechanism of redundancy with Hoxd13 unresolved\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Showed HOXA13 confers a distal positional identity and controls homophilic cell-adhesive properties, linking a transcription factor to mesenchymal cell sorting.\",\n      \"evidence\": \"Retroviral misexpression in chick limb bud plus in vitro cell dissociation/reassociation assays\",\n      \"pmids\": [\"7590231\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Adhesion molecules mediating sorting not identified\", \"Direct transcriptional targets unknown\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Connected HOXA13 loss-of-function mutation to a human Mendelian disease and to urogenital/vascular morphogenesis, defining the homeodomain as the critical functional element.\",\n      \"evidence\": \"HFGS family sequencing identifying a homeodomain-truncating nonsense mutation; Hoxa13 knockout urogenital/umbilical artery phenotyping\",\n      \"pmids\": [\"9020844\", \"9428414\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biochemical demonstration of lost DNA binding not shown\", \"Downstream targets in urogenital tract unidentified at this stage\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Defined the spectrum and distinct mechanisms of HFGS-causing mutations (nonsense, polyalanine expansion, recognition-helix missense), revealing that mutation class shapes phenotype severity.\",\n      \"evidence\": \"Sequencing of multiple HFGS families with genotype-phenotype correlation; comparative vertebrate sequence analysis of the N-terminal polyalanine region; Hypodactyly frameshift protein characterization\",\n      \"pmids\": [\"10839976\", \"10656931\", \"10625554\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional mechanism of missense allele inferred not demonstrated\", \"How polyalanine expansion impairs function not yet resolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identified the first direct effector pathway: HOXA13 regulates EphA7 to drive chondrogenic condensation, and established dominant Hoxa13 identity in limb and uterus via homeobox swap.\",\n      \"evidence\": \"Reciprocal genetics with EphA7 antibody-blocking in micromass culture; Hoxa11-to-Hoxa13 homeobox knock-in with expression profiling\",\n      \"pmids\": [\"11684655\", \"11688568\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct HOXA13 binding to EphA7 not yet shown at this stage\", \"Most of the >100 candidate targets uncharacterized\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Demonstrated that specific HFGS mutant proteins can act as dominant negatives in vivo and linked a recognition-helix missense allele to Guttmacher syndrome.\",\n      \"evidence\": \"Retroviral overexpression of HFGa13 in chick caudal endoderm; allele dissection in a Guttmacher syndrome family\",\n      \"pmids\": [\"11830557\", \"11968094\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Dominant-negative mechanism inferred from phenotype, not biochemistry\", \"Promoter deletion contribution to Guttmacher phenotype unclear\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Placed HOXA13 upstream of Fgf8/Bmp7 signaling in genital tubercle morphogenesis and showed it represses MyoD in limb muscle precursors.\",\n      \"evidence\": \"Hoxa13(GFP) mutant analysis with in vitro Fgf8 supplementation rescue; gain- and loss-of-function MyoD readout in chick and C2C12\",\n      \"pmids\": [\"12783783\", \"14706073\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding to Fgf8/Bmp7 or MyoD regulatory regions not shown\", \"Relationship between muscle and skeletal roles unclear\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Provided the first direct in vivo evidence that HOXA13 binds and activates BMP gene enhancers, and that polyalanine expansion causes loss of function via protein destabilization.\",\n      \"evidence\": \"Enhancer-binding assays and ChIP from autopod with BMP2/BMP7 rescue; polyalanine-expansion knock-in mouse dissecting RNA vs protein vs translation\",\n      \"pmids\": [\"15342482\", \"15385446\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Degradation machinery for expanded protein not identified\", \"Quantitative contribution of BMP targets to full phenotype incomplete\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Established the biochemical basis of HOXA13 specificity: direct EphA7 promoter regulation, MEIS cofactor interaction, and preference for AT-rich chromatin.\",\n      \"evidence\": \"ChIP and transactivation with binding-site mutagenesis on EphA7; yeast two-hybrid and Co-IP MEIS interaction mapping; CsCl-purified chromatin ChIP with AT-content analysis\",\n      \"pmids\": [\"16314414\", \"15617687\", \"16321965\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of MEIS interaction on target selection in vivo not resolved\", \"Genome-wide binding landscape not yet mapped\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined the high-affinity AT-rich binding consensus, added repression (Sostdc1) and vascular (EphA6/EphA7) targets, and linked polyalanine aggregates to sequestration of wild-type Hox proteins.\",\n      \"evidence\": \"SELEX binding-site determination with limb ChIP and reporter assays; genital tubercle ChIP for EphA6/EphA7; COS-cell aggregation and geldanamycin co-aggregation assays\",\n      \"pmids\": [\"17200107\", \"17304517\", \"17935235\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants of activation versus repression at AT-rich sites unclear\", \"Role of Hsp90 in vivo in HFGS not established\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Extended HOXA13 direct transcriptional control to placental labyrinth vasculature via Tie2 and Foxf1, with quantified high-affinity promoter binding.\",\n      \"evidence\": \"Hoxa13 mutant placenta microarray, placental ChIP, in vitro affinity measurement (Kd 27-42 nM), and reporter assays\",\n      \"pmids\": [\"18483557\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cofactor requirements for vascular target selection unknown\", \"Whether placental and limb targets share regulatory logic untested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Provided atomic-level mechanism of DNA recognition, showing HOXA13 binds as a dimer with defined residues required for binding, dimerization, and transactivation.\",\n      \"evidence\": \"NMR structure of the homeodomain-DNA complex with site-directed mutagenesis and dual binding/transcription assays\",\n      \"pmids\": [\"21829694\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of full-length protein with N-terminal region and cofactors absent\", \"Generality of dimeric binding across all targets untested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Linked HOXA13 to retinoic-acid-driven interdigital programmed cell death through direct Aldh1a2 regulation.\",\n      \"evidence\": \"Limb ChIP and reporter assays plus maternal RA supplementation rescue in Hoxa13 mutants\",\n      \"pmids\": [\"23553814\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interaction of RA pathway with BMP-dependent cell death not integrated\", \"Partial rescue indicates additional unidentified targets\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Mapped HOXA13 genome-wide binding in limb and revealed it transiently suspends cartilage differentiation by repressing pro-chondrogenic factors while validating enhancers near Bmp2 and Tshz2.\",\n      \"evidence\": \"ChIP-Seq with KO and double-KO transcriptomics and in vivo enhancer deletions; conditional KO defining Müllerian/ureter roles via Gata3\",\n      \"pmids\": [\"30895612\", \"30649340\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct versus indirect status of many repressed factors unresolved\", \"Temporal control of the differentiation switch mechanism incomplete\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Integrated HOXA13 into the digit-1 patterning network by showing it suppresses Gli3 transcription to permit 5'Hoxd expression.\",\n      \"evidence\": \"Hoxa13 mutant analysis with regulatory-element binding and in situ hybridization epistasis\",\n      \"pmids\": [\"31896583\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding to Gli3 regulatory sequences shown indirectly\", \"Interplay with Hoxd13 at this locus not fully dissected\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Documented HOXA13 as an oncogenic transcription factor in epithelial cancers, directly activating target genes that drive proliferation, metastasis, and chemoresistance.\",\n      \"evidence\": \"ChIP/luciferase identification of CDH17, FN1, ABCC4 as direct targets; epistatic rescue with ACLY/IGF1R; miRNA-mediated regulation of HOXA13\",\n      \"pmids\": [\"28387908\", \"35197128\", \"34094932\", \"34075028\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cofactor and chromatin context for cancer targets versus developmental targets unclear\", \"Most cancer findings from single labs without independent replication\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed that HOXA13 expression itself is controlled by a long-range repressive chromatin element at the HOXA locus, and that an oncogenic NUP98-HOXA13 fusion deregulates MSI2.\",\n      \"evidence\": \"Hi-C and CRISPR deletion of a 7p15.2 element with RNA-seq; ChIP of NUP98-HOXA13 fusion on the MSI2 promoter\",\n      \"pmids\": [\"29117547\", \"24971156\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of repressive loop formation undefined\", \"NUP98-HOXA13 target repertoire beyond MSI2 unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How HOXA13 selects activation versus repression at AT-rich sites, and how MEIS and chromatin context route the same DNA-binding activity to distinct developmental versus oncogenic gene programs, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of HOXA13-MEIS-DNA ternary complex\", \"Determinants distinguishing developmental from cancer target selection unknown\", \"Mechanism of polyalanine-driven degradation not molecularly defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [6, 12, 15, 16, 18, 20, 35]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [14, 15, 18, 19]},\n      {\"term_id\": \"GO:0003700\", \"supporting_discovery_ids\": [12, 19]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [17, 22]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [6, 12, 15, 18]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 2, 3, 4, 35]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 15, 20]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MEIS1\", \"MEIS2\", \"MEIS3\", \"HOXD13\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":8,"faith_pct":87.5}}