{"gene":"ACVRL1","run_date":"2026-06-09T22:02:40","timeline":{"discoveries":[{"year":2002,"finding":"Loss of Acvrl1 function in zebrafish (violet beauregarde mutants) causes increased endothelial cell number in specific cranial vessels, leading to dilated vessels and abnormal circulation, establishing that Acvrl1 normally restrains endothelial cell proliferation in arterial endothelium.","method":"Zebrafish forward genetic screen; positional cloning; loss-of-function mutant phenotypic analysis","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — positional cloning in a well-characterized zebrafish model with clear cellular phenotype (increased endothelial cell number), replicated in multiple subsequent studies confirming endothelial-autonomous role","pmids":["12050147"],"is_preprint":false},{"year":2010,"finding":"BMP9 is the specific activating ligand for ALK1/ACVRL1. All 19 tested HHT2-associated ALK1 mutant proteins were expressed; most reached the cell surface and retained BMP9 binding (except extracellular domain mutants), but the majority were defective in BMP9 downstream signaling (SMAD phosphorylation/transcriptional response). None of the ALK1 mutants exerted a dominant-negative effect on wild-type ALK1 activity, supporting a haploinsufficiency model for ACVRL1 mutations affecting BMP9 signaling.","method":"Cell transfection with 19 HHT2-associated ALK1 mutants; BMP9 binding assays; BMP9-stimulated SMAD signaling assays; dominant-negative functional testing","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — systematic in vitro functional analysis of 19 mutants with multiple orthogonal readouts (surface expression, ligand binding, signaling), identifying both loss-of-function mechanism and ruling out dominant-negative mechanism","pmids":["20501893"],"is_preprint":false},{"year":2014,"finding":"Endothelial-specific depletion of Acvrl1 in mice causes venous enlargement, vascular hyperbranching, and arteriovenous malformations, associated with loss of arterial Jag1 expression, decreased pSmad1/5/8 activity, and increased endothelial cell proliferation. Endoglin (Eng) expression was markedly down-regulated in Acvrl1-depleted endothelial cells, placing Eng expression downstream of Acvrl1 signaling in vivo.","method":"Conditional endothelial-specific Acvrl1 knockout mice (neonatal and adult); neonatal retinal plexus angiogenesis assay; immunohistochemistry for pSmad1/5/8, Jag1, Eng; endothelial cell proliferation quantification","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout with multiple orthogonal phenotypic and molecular readouts, endothelial-cell-autonomous mechanism established, endoglin placed downstream of Acvrl1 in vivo","pmids":["24896812"],"is_preprint":false},{"year":2013,"finding":"Glucocorticoids (e.g., dexamethasone) shift TGF-β signaling from the Tgfbr1/Smad2/3 axis to the Acvrl1/Smad1/5/8 axis in lung fibroblasts and endothelial cells by driving upregulation of the co-receptor Tgfbr3 (betaglycan), which acts as a switch. Acvrl1/Smad1 signaling, potentiated by dexamethasone, drives myofibroblast differentiation (smooth muscle actin and myosin acquisition) in a Smad1-dependent manner.","method":"Pharmacological treatment of NIH/3T3 cells, primary lung fibroblasts, smooth muscle cells, and endothelial cells; siRNA knockdown of Tgfbr3; phospho-Smad reporter assays; in vivo mouse dexamethasone administration; immunoblot for pSmad1 and smooth muscle markers","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple cell types, in vitro and in vivo confirmation, gene knockdown to establish Tgfbr3 as the molecular switch, multiple orthogonal readouts","pmids":["24347165"],"is_preprint":false},{"year":2010,"finding":"The ACVRL1 proximal promoter lacks TATA/CAAT boxes but contains multiple GC-rich Sp1 consensus sites; Sp1 is a key transcriptional activator of ACVRL1. In cells lacking Sp1, ACVRL1 promoter reporters show no significant activity; increasing Sp1 dose-dependently stimulates transcription. Chromatin immunoprecipitation identified multiple Sp1 binding sites in the endothelial ACVRL1 proximal promoter. CpG island methylation abolishes Sp1-dependent ACVRL1 transcriptional activation.","method":"5'RACE to identify new transcriptional start sites; promoter-reporter (luciferase) assays with Sp1 titration and Sp1 siRNA knockdown in HEK293T cells; chromatin immunoprecipitation (ChIP) in endothelial cells; in vitro CpG methylation of reporter constructs","journal":"BMC molecular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (reporter assay, siRNA knockdown, ChIP, methylation experiment) in one focused study of ACVRL1 transcriptional regulation","pmids":["20587022"],"is_preprint":false},{"year":2022,"finding":"FOXF1 transcription factor activates the BMP9/ACVRL1/SMAD1 signaling pathway in pulmonary endothelial progenitor cells (EPCs) to drive neonatal lung angiogenesis and alveolarization. FOXF1 synergizes with ETS transcription factor FLI1 to activate the ACVRL1 promoter. Nanoparticle-mediated silencing of ACVRL1 in newborn mice decreased neonatal lung angiogenesis and alveolarization; treatment with BMP9 restored these processes in ACVRL1-deficient mice.","method":"Single-cell RNA sequencing; conditional ACVRL1 silencing via nanoparticle delivery in newborn mice; BMP9 rescue experiments; FOXF1/FLI1 promoter activation assays; Foxf1 mutant mouse model (ACDMPV)","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo nanoparticle knockdown with phenotypic rescue by BMP9, promoter mechanistic studies, scRNA-seq pathway identification, multiple orthogonal methods in one study","pmids":["35440116"],"is_preprint":false},{"year":2019,"finding":"Somatic second-hit loss-of-function mutations in ACVRL1 (or ENG) were identified in 9/19 telangiectasia from HHT patients. Phase analysis confirmed that germline and somatic mutations exist in trans (on opposite alleles) in all 7 phaseable samples, supporting a Knudsonian two-hit mechanism requiring bi-allelic loss of ACVRL1 (or ENG) for telangiectasia formation, rather than simple haploinsufficiency.","method":"Next-generation sequencing of telangiectasia tissue; allele phasing of somatic and germline mutations","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — next-generation sequencing with allele phasing in multiple independent samples; mechanistic model (two-hit) established with direct molecular evidence","pmids":["31630786"],"is_preprint":false},{"year":2003,"finding":"Heterozygous loss-of-function mutation in Acvrl1 in mice causes age-dependent vascular lesions in skin, oral cavity, lung, liver, intestine, spleen, and brain, as well as gastrointestinal bleeding and secondary cardiac phenotype, recapitulating the HHT2 phenotype and establishing that haploinsufficiency of Acvrl1 is sufficient to cause vascular malformations in an age-dependent and tissue-specific manner.","method":"Acvrl1+/- heterozygous mouse model; histopathology; fecal occult blood testing; systematic organ examination","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — well-characterized in vivo haploinsufficiency mouse model with systematic phenotypic analysis across multiple organs, recapitulating human disease features","pmids":["12588795"],"is_preprint":false},{"year":2009,"finding":"Functional analysis of Drosophila saxophone (sax), the ortholog of human ACVRL1 (ALK1) and ACVR1 (ALK2), demonstrates that sax is an essential gene required for BMP signaling. Two gain-of-function sax alleles carry the same amino acid substitutions as human HHT2-causing ACVRL1 mutations, demonstrating that these mutations can cause gain-of-function activity in a heteromeric BMP receptor complex context. sax participates in a heteromeric receptor complex, consistent with ACVRL1's role in BMP type I receptor complexes.","method":"Drosophila genetics; generation and characterization of 15 sax alleles; epistasis analysis with BMP pathway components; reversion genetics; amino acid comparison with human ACVRL1 mutations","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — rigorous Drosophila genetic analysis with epistasis; ortholog status is somewhat ambiguous (sax is ortholog of both ALK1 and ALK2), single model organism study","pmids":["19620392"],"is_preprint":false},{"year":2013,"finding":"EDD (E3 ubiquitin ligase) negatively regulates ACVRL1 gene expression at the promoter level. Abrogation of EDD leads to upregulation of ACVRL1 and downstream SMAD signaling, resulting in deregulated vessel development and endothelial cell motility.","method":"Genome-wide chromatin binding profiling (ChIP-chip) and gene expression profiling integration; promoter reporter assays; EDD siRNA knockdown; endothelial cell motility and vessel development assays","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-based binding and expression profiling with functional validation by knockdown and phenotypic readout, single lab study","pmids":["24189493"],"is_preprint":false},{"year":2013,"finding":"An intron 6 mutation (c.772+27G>C) in ACVRL1 reduces ACVRL1 mRNA and protein expression in HHT2 patients. Luciferase reporter assays showed the mutation significantly reduces intronic transcriptional activity, and EMSA demonstrated that the mutation inhibits binding of transcription factor Sp1, establishing an Sp1-dependent intronic regulatory mechanism for ACVRL1 expression.","method":"RT-PCR and immunoblot quantification in patient-derived samples; luciferase reporter assay; electrophoretic mobility shift assay (EMSA) with Sp1","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (reporter assay, EMSA, patient samples), single lab study","pmids":["23460919"],"is_preprint":false},{"year":2015,"finding":"Functional and splicing analysis of 23 ACVRL1 mutations showed that 18/22 missense mutations abolish BMP9-stimulated signaling activity. One missense mutation (c.733A>G, p.Ile245Val) disrupts splicing of exon 6, and an intronic mutation (c.1048+5G>A) causes aberrant splicing, both leading to frameshift and premature stop codons with likely NMD-mediated mRNA degradation. These data confirm haploinsufficiency as the mechanism for HHT2, with affected alleles either losing receptor activity or undergoing mRNA degradation.","method":"BMP9-stimulated SMAD signaling assays; Western blot for protein maturation; fluorescence microscopy for protein localization; minigene splicing assay","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — systematic functional analysis of 23 mutations using multiple orthogonal methods (signaling assays, protein localization, splicing assays) establishing mechanistic basis for haploinsufficiency","pmids":["26176610"],"is_preprint":false},{"year":2016,"finding":"Four ACVRL1 missense mutations (p.V226M, p.G319R, p.R411W, p.R484W) identified in PAH patients markedly reduced Smad1/5 phosphorylation and luciferase reporter activities in BMP9-stimulated NIH-3T3 cells, demonstrating that these PAH-causing mutations significantly impair the BMP9/ALK1 signaling pathway.","method":"Transfection of ACVRL1 mutants into NIH-3T3 cells; BMP9 stimulation; phospho-Smad1/5 immunoblot; luciferase BMP reporter assay","journal":"Clinical science (London, England : 1979)","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro functional assays with multiple mutants and orthogonal readouts, single lab study","pmids":["27316748"],"is_preprint":false},{"year":2013,"finding":"ACVRL1 variant p.R218W (c.652C>T) identified in a vein of Galen aneurysmal malformation (VGAM) patient failed to promote SMAD1/5/8 phosphorylation upon BMP9 stimulation, whereas wild-type ALK1 enhanced phosphorylation. The R218W mutant also showed reduced transcriptional activation activity, establishing that loss of BMP9-mediated SMAD1/5/8 signaling is the mechanism by which this extracellular domain mutation causes vascular malformation.","method":"Immunoblotting for pSMAD1/5/8 after BMP9 stimulation in cells transfected with wild-type or mutant ACVRL1; transcriptional activation reporter assay","journal":"Journal of pediatric genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assays with orthogonal readouts (signaling and transcriptional), single lab, limited to one mutant","pmids":["27625857"],"is_preprint":false},{"year":2024,"finding":"Blood flow regulates acvrl1 transcription via ligand-dependent Alk1 activity in zebrafish. Acvrl1 expression in arterial endothelium requires blood flow and is rapidly restored after flow reinitiation. Loss of the circulating Alk1 ligand Bmp10 significantly decreases acvrl1 expression; intravascular injection of BMP10 or BMP9 in the absence of flow restores acvrl1 expression in an Alk1-dependent manner (not in alk1 mutants). Shear stress similarly increases ACVRL1 expression in human endothelial cells in an ALK1 ligand-dependent manner, suggesting a positive feedback loop: ligand-dependent ALK1 activity downstream of blood flow maintains ACVRL1 transcription.","method":"Zebrafish flow manipulation experiments; acvrl1:egfp transgenic reporter line; bmp10 mutant zebrafish; intravascular BMP9/BMP10 injection; human endothelial cell shear stress assay; RT-qPCR","journal":"Angiogenesis","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal in vivo and in vitro approaches including transgenic reporter, ligand injection rescue, genetic mutant, and human cell validation establishing the positive feedback mechanism","pmids":["38727966"],"is_preprint":false},{"year":2008,"finding":"Eng and Acvrl1 are co-expressed only in distal (pre-capillary) pulmonary arteries, distal veins, and capillaries in mouse lungs—not in proximal vessels. pSmad1/5/8 activity in distal arteries is specifically reduced in Eng+/- mice, consistent with Eng promoting Acvrl1-mediated Smad1/5/8 phosphorylation. Eng is more widely expressed than Acvrl1, being present also in proximal pulmonary veins, which may explain the higher frequency of AVMs in HHT1 patients.","method":"Immunohistochemistry; RT-PCR from laser-microdissected pulmonary arterial, venous, and capillary segments; pSmad1/5/8 immunostaining in Eng+/- and wild-type mice","journal":"Laboratory investigation; a journal of technical methods and pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — laser-microdissection RT-PCR and immunohistochemistry in Eng+/- mice with pSmad1/5/8 readout, single lab study","pmids":["19015642"],"is_preprint":false},{"year":2023,"finding":"ACVRL1 promotes resistance to multi-target tyrosine kinase inhibitors (mTKIs) in colorectal cancer through interaction with USP15 deubiquitinase and GPX2. The ACVRL1 truncation region (282–503 aa) directly interacts with GPX2. ACVRL1 recruits USP15, which deubiquitinates GPX2 at K187, leading to GPX2 protein stabilization and increased ROS clearance, decreased apoptosis, and mTKI resistance. The Wnt/β-catenin/KCNQ1OT1/miR-7-5p axis mediates ACVRL1 activation under mTKI treatment.","method":"LC-MS proteomics; co-immunoprecipitation; chromatin immunoprecipitation; ubiquitination assays; dual luciferase reporter; ACVRL1 truncation rescue experiments; CRISPR GPX2 knockout cell model with lysine mutants; in vitro and in vivo gain/loss-of-function","journal":"BMC medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, LC-MS, ubiquitination assay, truncation mapping, CRISPR rescue) in a single lab identifying a non-canonical ACVRL1 protein-protein interaction and mechanism","pmids":["37743483"],"is_preprint":false},{"year":2018,"finding":"Deep intronic variants within a ~300 bp CT-rich hotspot region of ACVRL1 intron 9 disrupt splicing and cause HHT in families who test negative for coding-region mutations, establishing this non-coding region as a functionally important regulatory element for ACVRL1 splicing. One family had an ACVRL1 intron 9:chromosome 3 translocation disrupting splicing.","method":"Whole genome sequencing; next-generation sequencing panel capturing coding and non-coding regions; RNA splicing analysis","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — WGS with RNA splicing validation in multiple unrelated families, single lab","pmids":["30244195"],"is_preprint":false}],"current_model":"ACVRL1/ALK1 encodes a TGF-β superfamily type I receptor, predominantly expressed in arterial endothelial cells, that functions as the primary signaling receptor for BMP9 (and BMP10) by forming a heteromeric complex and activating SMAD1/5/8 phosphorylation; ligand-dependent ALK1 activity downstream of blood flow maintains ACVRL1 transcription through a positive feedback loop, while transcription is also regulated by Sp1 binding to GC-rich promoter elements; loss of ACVRL1 function (via haploinsufficiency or somatic two-hit bi-allelic loss) causes arteriovenous malformations by failing to restrain endothelial cell proliferation, disrupting arterial identity (Jag1), reducing endoglin expression, and impairing BMP9/SMAD1 pathway activity in endothelial cells."},"narrative":{"mechanistic_narrative":"ACVRL1 (ALK1) encodes a TGF-β superfamily type I receptor that acts cell-autonomously in arterial endothelium to restrain endothelial cell proliferation and maintain vascular patterning, with its loss producing dilated vessels and arteriovenous malformations [PMID:12050147, PMID:24896812]. ALK1 functions as the specific signaling receptor for BMP9 (and the circulating ligand BMP10), driving phosphorylation of SMAD1/5/8 within a heteromeric BMP type I receptor complex [PMID:20501893, PMID:38727966, PMID:19620392]. Through this axis ALK1 sustains arterial identity (Jag1), supports endoglin (ENG) expression, and limits endothelial proliferation; ENG and ALK1 co-act in distal vessels to promote SMAD1/5/8 activity [PMID:24896812, PMID:19015642]. ALK1 signaling is essential for developmental angiogenesis, exemplified by FOXF1/FLI1-driven activation of the BMP9/ACVRL1/SMAD1 pathway in neonatal lung angiogenesis and alveolarization, where exogenous BMP9 rescues ACVRL1-deficient phenotypes [PMID:35440116]. ACVRL1 transcription is governed by Sp1 acting at GC-rich promoter and intronic elements, repressed by CpG methylation and the E3 ligase EDD, and reinforced by a flow-dependent positive feedback loop in which ligand-activated ALK1 downstream of blood flow maintains its own expression [PMID:20587022, PMID:24189493, PMID:23460919, PMID:38727966]. Heterozygous loss-of-function causes hereditary hemorrhagic telangiectasia type 2 (HHT2) through haploinsufficiency, with disease-associated mutations abolishing BMP9-stimulated signaling or undergoing NMD-mediated degradation, while somatic second-hit mutations in trans produce Knudsonian bi-allelic loss in telangiectasia lesions; ACVRL1 mutations also cause pulmonary arterial hypertension and vein of Galen aneurysmal malformation by impairing BMP9/ALK1 signaling [PMID:20501893, PMID:31630786, PMID:12588795, PMID:26176610, PMID:27316748, PMID:27625857].","teleology":[{"year":2002,"claim":"Established the cellular role of Acvrl1 in vivo, showing it normally restrains endothelial cell proliferation in arterial endothelium rather than acting only as a generic signaling component.","evidence":"Zebrafish forward genetic screen and positional cloning of violet beauregarde loss-of-function mutants","pmids":["12050147"],"confidence":"High","gaps":["Did not identify the activating ligand or downstream SMAD effectors","Mechanism linking proliferation control to vessel patterning unresolved"]},{"year":2003,"claim":"Demonstrated that haploinsufficiency of Acvrl1 is sufficient to recapitulate HHT2, establishing dosage sensitivity as the disease mechanism in a mammalian system.","evidence":"Acvrl1+/- heterozygous mouse model with systematic multi-organ histopathology","pmids":["12588795"],"confidence":"High","gaps":["Did not explain age-dependence or tissue specificity of lesions","Molecular events downstream of reduced dosage not defined"]},{"year":2008,"claim":"Linked Eng and Acvrl1 spatially, showing co-expression in distal vessels and Eng-dependent maintenance of pSmad1/5/8, framing endoglin as a partner in ALK1-mediated signaling.","evidence":"Laser-microdissection RT-PCR and pSmad1/5/8 immunohistochemistry in Eng+/- and wild-type mouse lung","pmids":["19015642"],"confidence":"Medium","gaps":["Correlative co-expression without direct biochemical demonstration of an ENG-ALK1 complex","Single lab, limited to lung vasculature"]},{"year":2009,"claim":"Used Drosophila genetics to place the ALK1 ortholog within a heteromeric BMP receptor complex and to show that HHT2-equivalent substitutions can confer gain-of-function in that context.","evidence":"Generation and epistasis analysis of 15 saxophone alleles with comparison to human ACVRL1 mutations","pmids":["19620392"],"confidence":"Medium","gaps":["sax is ortholog of both ALK1 and ALK2, complicating direct assignment","Gain-of-function inference not confirmed for human ALK1 in mammalian cells"]},{"year":2010,"claim":"Identified BMP9 as the specific activating ligand and systematically established loss-of-function/haploinsufficiency as the mechanism, while ruling out dominant-negative action of HHT2 mutants.","evidence":"Transfection of 19 HHT2 ALK1 mutants with BMP9 binding, SMAD signaling, and dominant-negative assays","pmids":["20501893"],"confidence":"High","gaps":["Did not address in vivo ligand availability or BMP10 contribution","Receptor complex stoichiometry not resolved"]},{"year":2010,"claim":"Defined the transcriptional control of ACVRL1, showing Sp1 binding to GC-rich promoter elements drives expression and that CpG methylation silences it.","evidence":"5'RACE, Sp1-titration and siRNA luciferase reporter assays, ChIP, and in vitro promoter methylation","pmids":["20587022"],"confidence":"High","gaps":["Did not connect Sp1 regulation to endothelial-specific or flow-responsive expression","Upstream signals controlling Sp1 activity at this promoter unknown"]},{"year":2013,"claim":"Extended ACVRL1 regulation to an intronic Sp1-dependent element, showing a disease-associated intron 6 variant reduces expression by abolishing Sp1 binding.","evidence":"Patient-sample RT-PCR/immunoblot, luciferase reporter, and Sp1 EMSA","pmids":["23460919"],"confidence":"Medium","gaps":["Single variant in a single lab","Quantitative contribution of the intronic element to total expression unclear"]},{"year":2013,"claim":"Identified EDD as a negative transcriptional regulator of ACVRL1, adding a brake on expression whose loss deregulates SMAD signaling and vessel development.","evidence":"ChIP-chip/expression profiling integration with EDD siRNA knockdown and endothelial motility assays","pmids":["24189493"],"confidence":"Medium","gaps":["Mechanism by which EDD represses the promoter not detailed","Single lab without independent confirmation"]},{"year":2013,"claim":"Revealed a glucocorticoid-driven switch, via Tgfbr3 upregulation, that diverts TGF-β signaling into the Acvrl1/Smad1/5/8 axis to promote myofibroblast differentiation.","evidence":"Pharmacological and siRNA Tgfbr3 knockdown studies across multiple cell types with in vivo dexamethasone and phospho-Smad readouts","pmids":["24347165"],"confidence":"High","gaps":["Relevance to endothelial/vascular ALK1 function not established","Direct interaction between Tgfbr3 and ALK1 not biochemically mapped"]},{"year":2013,"claim":"Connected ALK1 dysfunction to vein of Galen aneurysmal malformation by showing an extracellular-domain variant abolishes BMP9-stimulated SMAD1/5/8 phosphorylation.","evidence":"pSMAD1/5/8 immunoblotting and transcriptional reporter assays for wild-type versus R218W ALK1 after BMP9 stimulation","pmids":["27625857"],"confidence":"Medium","gaps":["Single mutant in a single patient context","Causality at the organismal level not demonstrated"]},{"year":2014,"claim":"Established the endothelial-cell-autonomous in vivo mechanism, placing Jag1 (arterial identity), endoglin expression, and proliferation control downstream of Acvrl1/Smad1/5/8.","evidence":"Conditional endothelial-specific Acvrl1 knockout mice with retinal angiogenesis, pSmad1/5/8, Jag1, and Eng readouts","pmids":["24896812"],"confidence":"High","gaps":["Did not define how SMAD targets coordinate arterial identity with proliferation","Direct transcriptional targets of the pathway not mapped"]},{"year":2015,"claim":"Consolidated the haploinsufficiency mechanism across many mutations, showing both loss of receptor signaling activity and splicing/NMD-mediated allele loss.","evidence":"BMP9 signaling, protein maturation/localization, and minigene splicing assays of 23 ACVRL1 mutations","pmids":["26176610"],"confidence":"High","gaps":["Did not address modifiers explaining variable HHT2 expressivity","In vivo consequences of NMD alleles not tested"]},{"year":2016,"claim":"Broadened the disease spectrum by showing PAH-associated ACVRL1 missense mutations impair BMP9/ALK1 SMAD1/5 signaling.","evidence":"BMP9-stimulated phospho-Smad1/5 immunoblot and luciferase reporter assays of four PAH mutants in NIH-3T3 cells","pmids":["27316748"],"confidence":"Medium","gaps":["In vitro overexpression system, single lab","Vascular-bed-specific basis of PAH versus HHT phenotypes unresolved"]},{"year":2018,"claim":"Identified non-coding intron 9 as a functionally important splicing-regulatory region, explaining HHT in coding-mutation-negative families.","evidence":"Whole genome sequencing and RNA splicing analysis across multiple unrelated families","pmids":["30244195"],"confidence":"Medium","gaps":["Precise cis-elements and trans-factors within the hotspot not defined","Single lab cohort"]},{"year":2019,"claim":"Refined the disease model from simple haploinsufficiency to a Knudsonian two-hit mechanism, demonstrating somatic second-hit mutations in trans within telangiectasia lesions.","evidence":"Next-generation sequencing of telangiectasia tissue with allele phasing of germline and somatic mutations","pmids":["31630786"],"confidence":"High","gaps":["Why focal bi-allelic loss occurs at specific sites unknown","Reconciliation with germline haploinsufficiency models incomplete"]},{"year":2022,"claim":"Positioned ACVRL1 in a developmental transcriptional circuit, showing FOXF1/FLI1 activate the BMP9/ACVRL1/SMAD1 pathway to drive neonatal lung angiogenesis with BMP9 rescue.","evidence":"scRNA-seq, nanoparticle ACVRL1 silencing in newborn mice, FOXF1/FLI1 promoter assays, and BMP9 rescue","pmids":["35440116"],"confidence":"High","gaps":["Direct FOXF1/FLI1 binding sites on the ACVRL1 promoter not finely mapped","Generalizability beyond neonatal lung not addressed"]},{"year":2023,"claim":"Uncovered a non-canonical, SMAD-independent ACVRL1 function in cancer, where it scaffolds USP15-mediated deubiquitination of GPX2 to confer tyrosine kinase inhibitor resistance.","evidence":"LC-MS, Co-IP, truncation mapping, ubiquitination assays, and CRISPR GPX2 lysine-mutant rescue in colorectal cancer models","pmids":["37743483"],"confidence":"Medium","gaps":["Single lab; reciprocal validation of the ACVRL1-GPX2-USP15 interactions limited","Relationship to canonical receptor signaling unclear"]},{"year":2024,"claim":"Defined a flow-driven positive feedback loop in which ligand (BMP10/BMP9)-dependent ALK1 activity downstream of blood flow maintains acvrl1 transcription.","evidence":"Zebrafish flow manipulation, acvrl1:egfp reporter, bmp10 mutants, intravascular BMP9/BMP10 rescue, and human endothelial shear-stress assays","pmids":["38727966"],"confidence":"High","gaps":["Transcription factors transducing the flow/ALK1 signal to the promoter not identified","Quantitative dynamics of the feedback loop not modeled"]},{"year":null,"claim":"How ALK1/SMAD1/5/8 output is converted into specific transcriptional programs controlling arterial identity, proliferation, and lesion formation, and which downstream effectors integrate flow, ligand, and ENG inputs, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["Direct SMAD target genes coordinating arterial identity and proliferation not mapped","Mechanism reconciling haploinsufficiency with focal two-hit lesion formation incomplete","Structural basis of BMP9/BMP10-ALK1-ENG complex assembly not defined in the corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,2,11]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[1,14]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[1,2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,11]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,2,14]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,2,5]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[4,9,10]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[6,7,11,12]}],"complexes":["BMP type I receptor complex"],"partners":["BMP9","BMP10","ENG","TGFBR3","USP15","GPX2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P37023","full_name":"Activin receptor type-1-like","aliases":["Activin receptor-like kinase 1","ALK-1","Serine/threonine-protein kinase receptor R3","SKR3","TGF-B superfamily receptor type I","TSR-I"],"length_aa":503,"mass_kda":56.1,"function":"Type I receptor for TGF-beta family ligands BMP9/GDF2 and BMP10 and important regulator of normal blood vessel development. On ligand binding, forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases. Type II receptors phosphorylate and activate type I receptors which autophosphorylate, then bind and activate SMAD transcriptional regulators. 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analysis","url":"https://pubmed.ncbi.nlm.nih.gov/35908770","citation_count":10,"is_preprint":false},{"pmid":"32170914","id":"PMC_32170914","title":"An ACVRL1 gene mutation presenting as vein of Galen malformation at prenatal diagnosis.","date":"2020","source":"American journal of medical genetics. 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from coding DNA.","date":"2023","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/37816352","citation_count":9,"is_preprint":false},{"pmid":"18198127","id":"PMC_18198127","title":"Studies on membrane-associated prostaglandin E synthase-2 with reference to production of 12L-hydroxy-5,8,10-heptadecatrienoic acid (HHT).","date":"2008","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/18198127","citation_count":9,"is_preprint":false},{"pmid":"38727966","id":"PMC_38727966","title":"Blood flow regulates acvrl1 transcription via ligand-dependent Alk1 activity.","date":"2024","source":"Angiogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/38727966","citation_count":8,"is_preprint":false},{"pmid":"16829353","id":"PMC_16829353","title":"Hereditary hemorrhagic telangiectasia is caused by the Q490X mutation of the ACVRL1 gene in a large Arab family: support of homozygous lethality.","date":"2005","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16829353","citation_count":8,"is_preprint":false},{"pmid":"29147802","id":"PMC_29147802","title":"Executive summary of the 12th HHT international scientific conference.","date":"2018","source":"Angiogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/29147802","citation_count":8,"is_preprint":false},{"pmid":"19270816","id":"PMC_19270816","title":"Clinical features and mutations in the ENG, ACVRL1, and SMAD4 genes in Korean patients with hereditary hemorrhagic telangiectasia.","date":"2009","source":"Journal of Korean medical science","url":"https://pubmed.ncbi.nlm.nih.gov/19270816","citation_count":8,"is_preprint":false},{"pmid":"39939156","id":"PMC_39939156","title":"Arteriovenous malformation from a patient with JP-HHT harbours two second-hit somatic DNA alterations in SMAD4.","date":"2025","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39939156","citation_count":8,"is_preprint":false},{"pmid":"32106460","id":"PMC_32106460","title":"Analysis of the Complete Genome of the Alkaliphilic and Phototrophic Firmicute Heliorestis convoluta Strain HHT.","date":"2020","source":"Microorganisms","url":"https://pubmed.ncbi.nlm.nih.gov/32106460","citation_count":8,"is_preprint":false},{"pmid":"32962750","id":"PMC_32962750","title":"Sequence variations of ACVRL1 play a critical role in hepatic vascular malformations in hereditary hemorrhagic telangiectasia.","date":"2020","source":"Orphanet journal of rare diseases","url":"https://pubmed.ncbi.nlm.nih.gov/32962750","citation_count":7,"is_preprint":false},{"pmid":"27316748","id":"PMC_27316748","title":"Identification of multiple ACVRL1 mutations in patients with pulmonary arterial hypertension by targeted exome capture.","date":"2016","source":"Clinical science (London, England : 1979)","url":"https://pubmed.ncbi.nlm.nih.gov/27316748","citation_count":7,"is_preprint":false},{"pmid":"29843236","id":"PMC_29843236","title":"Immunohistochemical Analysis of Activin Receptor-Like Kinase 1 (ACVRL1/ALK1) Expression in the Rat and Human Hippocampus: Decline in CA3 During Progression of Alzheimer's Disease.","date":"2018","source":"Journal of Alzheimer's disease : JAD","url":"https://pubmed.ncbi.nlm.nih.gov/29843236","citation_count":7,"is_preprint":false},{"pmid":"31360828","id":"PMC_31360828","title":"Topically Applied Etamsylate: A New Orphan Drug for HHT-Derived Epistaxis (Antiangiogenesis through FGF Pathway Inhibition).","date":"2019","source":"TH open : companion journal to thrombosis and haemostasis","url":"https://pubmed.ncbi.nlm.nih.gov/31360828","citation_count":7,"is_preprint":false},{"pmid":"40225928","id":"PMC_40225928","title":"Specifications of the ACMG/AMP Variant Curation Guidelines for Hereditary Hemorrhagic Telangiectasia Genes-ENG and ACVRL1.","date":"2024","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/40225928","citation_count":6,"is_preprint":false},{"pmid":"40964703","id":"PMC_40964703","title":"Hereditary Hemorrhagic Telangiectasia Prevalence Estimates Calculated From GnomAD Allele Frequencies of Predicted Pathogenic Variants in ENG and ACVRL1.","date":"2025","source":"Circulation. Genomic and precision medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40964703","citation_count":6,"is_preprint":false},{"pmid":"37371070","id":"PMC_37371070","title":"Generation of a Syngeneic Heterozygous ACVRL1 Knockout iPS Cell Line for the In Vitro Study of HHT2-Associated Angiogenesis.","date":"2023","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/37371070","citation_count":5,"is_preprint":false},{"pmid":"36081671","id":"PMC_36081671","title":"Characterization of the Newly Established Homoharringtonine- (HHT-) Resistant Cell Lines and Mechanisms of Resistance.","date":"2022","source":"Journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36081671","citation_count":5,"is_preprint":false},{"pmid":"34161796","id":"PMC_34161796","title":"12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid (12-HHT) induces cell growth and improves barrier function through BLT2 interaction in intestinal epithelial Caco-2 cell cultures.","date":"2021","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/34161796","citation_count":5,"is_preprint":false},{"pmid":"25981877","id":"PMC_25981877","title":"Metformin as possible therapy of pulmonary arterio venous malformation in HHT patients.","date":"2015","source":"Medical hypotheses","url":"https://pubmed.ncbi.nlm.nih.gov/25981877","citation_count":5,"is_preprint":false},{"pmid":"31022982","id":"PMC_31022982","title":"The 12-HHT/BLT2/NO Axis Is Associated to the Wound Healing and Skin Condition in Different Glycaemic States.","date":"2019","source":"Medical sciences (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/31022982","citation_count":5,"is_preprint":false},{"pmid":"1684633","id":"PMC_1684633","title":"Purification and characterization of dipeptidyl peptidase IV from Streptococcus salivarius HHT.","date":"1991","source":"Microbios","url":"https://pubmed.ncbi.nlm.nih.gov/1684633","citation_count":5,"is_preprint":false},{"pmid":"29305977","id":"PMC_29305977","title":"Functional analysis of a novel ENG variant in a patient with hereditary hemorrhagic telangiectasia (HHT) identifies a new Sp1 binding-site.","date":"2018","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/29305977","citation_count":5,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":53321,"output_tokens":5654,"usd":0.122386,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14107,"output_tokens":5470,"usd":0.103642,"stage2_stop_reason":"end_turn"},"total_usd":0.226028,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"Loss of Acvrl1 function in zebrafish (violet beauregarde mutants) causes increased endothelial cell number in specific cranial vessels, leading to dilated vessels and abnormal circulation, establishing that Acvrl1 normally restrains endothelial cell proliferation in arterial endothelium.\",\n      \"method\": \"Zebrafish forward genetic screen; positional cloning; loss-of-function mutant phenotypic analysis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — positional cloning in a well-characterized zebrafish model with clear cellular phenotype (increased endothelial cell number), replicated in multiple subsequent studies confirming endothelial-autonomous role\",\n      \"pmids\": [\"12050147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"BMP9 is the specific activating ligand for ALK1/ACVRL1. All 19 tested HHT2-associated ALK1 mutant proteins were expressed; most reached the cell surface and retained BMP9 binding (except extracellular domain mutants), but the majority were defective in BMP9 downstream signaling (SMAD phosphorylation/transcriptional response). None of the ALK1 mutants exerted a dominant-negative effect on wild-type ALK1 activity, supporting a haploinsufficiency model for ACVRL1 mutations affecting BMP9 signaling.\",\n      \"method\": \"Cell transfection with 19 HHT2-associated ALK1 mutants; BMP9 binding assays; BMP9-stimulated SMAD signaling assays; dominant-negative functional testing\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — systematic in vitro functional analysis of 19 mutants with multiple orthogonal readouts (surface expression, ligand binding, signaling), identifying both loss-of-function mechanism and ruling out dominant-negative mechanism\",\n      \"pmids\": [\"20501893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Endothelial-specific depletion of Acvrl1 in mice causes venous enlargement, vascular hyperbranching, and arteriovenous malformations, associated with loss of arterial Jag1 expression, decreased pSmad1/5/8 activity, and increased endothelial cell proliferation. Endoglin (Eng) expression was markedly down-regulated in Acvrl1-depleted endothelial cells, placing Eng expression downstream of Acvrl1 signaling in vivo.\",\n      \"method\": \"Conditional endothelial-specific Acvrl1 knockout mice (neonatal and adult); neonatal retinal plexus angiogenesis assay; immunohistochemistry for pSmad1/5/8, Jag1, Eng; endothelial cell proliferation quantification\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout with multiple orthogonal phenotypic and molecular readouts, endothelial-cell-autonomous mechanism established, endoglin placed downstream of Acvrl1 in vivo\",\n      \"pmids\": [\"24896812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Glucocorticoids (e.g., dexamethasone) shift TGF-β signaling from the Tgfbr1/Smad2/3 axis to the Acvrl1/Smad1/5/8 axis in lung fibroblasts and endothelial cells by driving upregulation of the co-receptor Tgfbr3 (betaglycan), which acts as a switch. Acvrl1/Smad1 signaling, potentiated by dexamethasone, drives myofibroblast differentiation (smooth muscle actin and myosin acquisition) in a Smad1-dependent manner.\",\n      \"method\": \"Pharmacological treatment of NIH/3T3 cells, primary lung fibroblasts, smooth muscle cells, and endothelial cells; siRNA knockdown of Tgfbr3; phospho-Smad reporter assays; in vivo mouse dexamethasone administration; immunoblot for pSmad1 and smooth muscle markers\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple cell types, in vitro and in vivo confirmation, gene knockdown to establish Tgfbr3 as the molecular switch, multiple orthogonal readouts\",\n      \"pmids\": [\"24347165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The ACVRL1 proximal promoter lacks TATA/CAAT boxes but contains multiple GC-rich Sp1 consensus sites; Sp1 is a key transcriptional activator of ACVRL1. In cells lacking Sp1, ACVRL1 promoter reporters show no significant activity; increasing Sp1 dose-dependently stimulates transcription. Chromatin immunoprecipitation identified multiple Sp1 binding sites in the endothelial ACVRL1 proximal promoter. CpG island methylation abolishes Sp1-dependent ACVRL1 transcriptional activation.\",\n      \"method\": \"5'RACE to identify new transcriptional start sites; promoter-reporter (luciferase) assays with Sp1 titration and Sp1 siRNA knockdown in HEK293T cells; chromatin immunoprecipitation (ChIP) in endothelial cells; in vitro CpG methylation of reporter constructs\",\n      \"journal\": \"BMC molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (reporter assay, siRNA knockdown, ChIP, methylation experiment) in one focused study of ACVRL1 transcriptional regulation\",\n      \"pmids\": [\"20587022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FOXF1 transcription factor activates the BMP9/ACVRL1/SMAD1 signaling pathway in pulmonary endothelial progenitor cells (EPCs) to drive neonatal lung angiogenesis and alveolarization. FOXF1 synergizes with ETS transcription factor FLI1 to activate the ACVRL1 promoter. Nanoparticle-mediated silencing of ACVRL1 in newborn mice decreased neonatal lung angiogenesis and alveolarization; treatment with BMP9 restored these processes in ACVRL1-deficient mice.\",\n      \"method\": \"Single-cell RNA sequencing; conditional ACVRL1 silencing via nanoparticle delivery in newborn mice; BMP9 rescue experiments; FOXF1/FLI1 promoter activation assays; Foxf1 mutant mouse model (ACDMPV)\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo nanoparticle knockdown with phenotypic rescue by BMP9, promoter mechanistic studies, scRNA-seq pathway identification, multiple orthogonal methods in one study\",\n      \"pmids\": [\"35440116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Somatic second-hit loss-of-function mutations in ACVRL1 (or ENG) were identified in 9/19 telangiectasia from HHT patients. Phase analysis confirmed that germline and somatic mutations exist in trans (on opposite alleles) in all 7 phaseable samples, supporting a Knudsonian two-hit mechanism requiring bi-allelic loss of ACVRL1 (or ENG) for telangiectasia formation, rather than simple haploinsufficiency.\",\n      \"method\": \"Next-generation sequencing of telangiectasia tissue; allele phasing of somatic and germline mutations\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — next-generation sequencing with allele phasing in multiple independent samples; mechanistic model (two-hit) established with direct molecular evidence\",\n      \"pmids\": [\"31630786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Heterozygous loss-of-function mutation in Acvrl1 in mice causes age-dependent vascular lesions in skin, oral cavity, lung, liver, intestine, spleen, and brain, as well as gastrointestinal bleeding and secondary cardiac phenotype, recapitulating the HHT2 phenotype and establishing that haploinsufficiency of Acvrl1 is sufficient to cause vascular malformations in an age-dependent and tissue-specific manner.\",\n      \"method\": \"Acvrl1+/- heterozygous mouse model; histopathology; fecal occult blood testing; systematic organ examination\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — well-characterized in vivo haploinsufficiency mouse model with systematic phenotypic analysis across multiple organs, recapitulating human disease features\",\n      \"pmids\": [\"12588795\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Functional analysis of Drosophila saxophone (sax), the ortholog of human ACVRL1 (ALK1) and ACVR1 (ALK2), demonstrates that sax is an essential gene required for BMP signaling. Two gain-of-function sax alleles carry the same amino acid substitutions as human HHT2-causing ACVRL1 mutations, demonstrating that these mutations can cause gain-of-function activity in a heteromeric BMP receptor complex context. sax participates in a heteromeric receptor complex, consistent with ACVRL1's role in BMP type I receptor complexes.\",\n      \"method\": \"Drosophila genetics; generation and characterization of 15 sax alleles; epistasis analysis with BMP pathway components; reversion genetics; amino acid comparison with human ACVRL1 mutations\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — rigorous Drosophila genetic analysis with epistasis; ortholog status is somewhat ambiguous (sax is ortholog of both ALK1 and ALK2), single model organism study\",\n      \"pmids\": [\"19620392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"EDD (E3 ubiquitin ligase) negatively regulates ACVRL1 gene expression at the promoter level. Abrogation of EDD leads to upregulation of ACVRL1 and downstream SMAD signaling, resulting in deregulated vessel development and endothelial cell motility.\",\n      \"method\": \"Genome-wide chromatin binding profiling (ChIP-chip) and gene expression profiling integration; promoter reporter assays; EDD siRNA knockdown; endothelial cell motility and vessel development assays\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-based binding and expression profiling with functional validation by knockdown and phenotypic readout, single lab study\",\n      \"pmids\": [\"24189493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"An intron 6 mutation (c.772+27G>C) in ACVRL1 reduces ACVRL1 mRNA and protein expression in HHT2 patients. Luciferase reporter assays showed the mutation significantly reduces intronic transcriptional activity, and EMSA demonstrated that the mutation inhibits binding of transcription factor Sp1, establishing an Sp1-dependent intronic regulatory mechanism for ACVRL1 expression.\",\n      \"method\": \"RT-PCR and immunoblot quantification in patient-derived samples; luciferase reporter assay; electrophoretic mobility shift assay (EMSA) with Sp1\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (reporter assay, EMSA, patient samples), single lab study\",\n      \"pmids\": [\"23460919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Functional and splicing analysis of 23 ACVRL1 mutations showed that 18/22 missense mutations abolish BMP9-stimulated signaling activity. One missense mutation (c.733A>G, p.Ile245Val) disrupts splicing of exon 6, and an intronic mutation (c.1048+5G>A) causes aberrant splicing, both leading to frameshift and premature stop codons with likely NMD-mediated mRNA degradation. These data confirm haploinsufficiency as the mechanism for HHT2, with affected alleles either losing receptor activity or undergoing mRNA degradation.\",\n      \"method\": \"BMP9-stimulated SMAD signaling assays; Western blot for protein maturation; fluorescence microscopy for protein localization; minigene splicing assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — systematic functional analysis of 23 mutations using multiple orthogonal methods (signaling assays, protein localization, splicing assays) establishing mechanistic basis for haploinsufficiency\",\n      \"pmids\": [\"26176610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Four ACVRL1 missense mutations (p.V226M, p.G319R, p.R411W, p.R484W) identified in PAH patients markedly reduced Smad1/5 phosphorylation and luciferase reporter activities in BMP9-stimulated NIH-3T3 cells, demonstrating that these PAH-causing mutations significantly impair the BMP9/ALK1 signaling pathway.\",\n      \"method\": \"Transfection of ACVRL1 mutants into NIH-3T3 cells; BMP9 stimulation; phospho-Smad1/5 immunoblot; luciferase BMP reporter assay\",\n      \"journal\": \"Clinical science (London, England : 1979)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro functional assays with multiple mutants and orthogonal readouts, single lab study\",\n      \"pmids\": [\"27316748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ACVRL1 variant p.R218W (c.652C>T) identified in a vein of Galen aneurysmal malformation (VGAM) patient failed to promote SMAD1/5/8 phosphorylation upon BMP9 stimulation, whereas wild-type ALK1 enhanced phosphorylation. The R218W mutant also showed reduced transcriptional activation activity, establishing that loss of BMP9-mediated SMAD1/5/8 signaling is the mechanism by which this extracellular domain mutation causes vascular malformation.\",\n      \"method\": \"Immunoblotting for pSMAD1/5/8 after BMP9 stimulation in cells transfected with wild-type or mutant ACVRL1; transcriptional activation reporter assay\",\n      \"journal\": \"Journal of pediatric genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assays with orthogonal readouts (signaling and transcriptional), single lab, limited to one mutant\",\n      \"pmids\": [\"27625857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Blood flow regulates acvrl1 transcription via ligand-dependent Alk1 activity in zebrafish. Acvrl1 expression in arterial endothelium requires blood flow and is rapidly restored after flow reinitiation. Loss of the circulating Alk1 ligand Bmp10 significantly decreases acvrl1 expression; intravascular injection of BMP10 or BMP9 in the absence of flow restores acvrl1 expression in an Alk1-dependent manner (not in alk1 mutants). Shear stress similarly increases ACVRL1 expression in human endothelial cells in an ALK1 ligand-dependent manner, suggesting a positive feedback loop: ligand-dependent ALK1 activity downstream of blood flow maintains ACVRL1 transcription.\",\n      \"method\": \"Zebrafish flow manipulation experiments; acvrl1:egfp transgenic reporter line; bmp10 mutant zebrafish; intravascular BMP9/BMP10 injection; human endothelial cell shear stress assay; RT-qPCR\",\n      \"journal\": \"Angiogenesis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal in vivo and in vitro approaches including transgenic reporter, ligand injection rescue, genetic mutant, and human cell validation establishing the positive feedback mechanism\",\n      \"pmids\": [\"38727966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Eng and Acvrl1 are co-expressed only in distal (pre-capillary) pulmonary arteries, distal veins, and capillaries in mouse lungs—not in proximal vessels. pSmad1/5/8 activity in distal arteries is specifically reduced in Eng+/- mice, consistent with Eng promoting Acvrl1-mediated Smad1/5/8 phosphorylation. Eng is more widely expressed than Acvrl1, being present also in proximal pulmonary veins, which may explain the higher frequency of AVMs in HHT1 patients.\",\n      \"method\": \"Immunohistochemistry; RT-PCR from laser-microdissected pulmonary arterial, venous, and capillary segments; pSmad1/5/8 immunostaining in Eng+/- and wild-type mice\",\n      \"journal\": \"Laboratory investigation; a journal of technical methods and pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — laser-microdissection RT-PCR and immunohistochemistry in Eng+/- mice with pSmad1/5/8 readout, single lab study\",\n      \"pmids\": [\"19015642\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ACVRL1 promotes resistance to multi-target tyrosine kinase inhibitors (mTKIs) in colorectal cancer through interaction with USP15 deubiquitinase and GPX2. The ACVRL1 truncation region (282–503 aa) directly interacts with GPX2. ACVRL1 recruits USP15, which deubiquitinates GPX2 at K187, leading to GPX2 protein stabilization and increased ROS clearance, decreased apoptosis, and mTKI resistance. The Wnt/β-catenin/KCNQ1OT1/miR-7-5p axis mediates ACVRL1 activation under mTKI treatment.\",\n      \"method\": \"LC-MS proteomics; co-immunoprecipitation; chromatin immunoprecipitation; ubiquitination assays; dual luciferase reporter; ACVRL1 truncation rescue experiments; CRISPR GPX2 knockout cell model with lysine mutants; in vitro and in vivo gain/loss-of-function\",\n      \"journal\": \"BMC medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, LC-MS, ubiquitination assay, truncation mapping, CRISPR rescue) in a single lab identifying a non-canonical ACVRL1 protein-protein interaction and mechanism\",\n      \"pmids\": [\"37743483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Deep intronic variants within a ~300 bp CT-rich hotspot region of ACVRL1 intron 9 disrupt splicing and cause HHT in families who test negative for coding-region mutations, establishing this non-coding region as a functionally important regulatory element for ACVRL1 splicing. One family had an ACVRL1 intron 9:chromosome 3 translocation disrupting splicing.\",\n      \"method\": \"Whole genome sequencing; next-generation sequencing panel capturing coding and non-coding regions; RNA splicing analysis\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — WGS with RNA splicing validation in multiple unrelated families, single lab\",\n      \"pmids\": [\"30244195\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ACVRL1/ALK1 encodes a TGF-β superfamily type I receptor, predominantly expressed in arterial endothelial cells, that functions as the primary signaling receptor for BMP9 (and BMP10) by forming a heteromeric complex and activating SMAD1/5/8 phosphorylation; ligand-dependent ALK1 activity downstream of blood flow maintains ACVRL1 transcription through a positive feedback loop, while transcription is also regulated by Sp1 binding to GC-rich promoter elements; loss of ACVRL1 function (via haploinsufficiency or somatic two-hit bi-allelic loss) causes arteriovenous malformations by failing to restrain endothelial cell proliferation, disrupting arterial identity (Jag1), reducing endoglin expression, and impairing BMP9/SMAD1 pathway activity in endothelial cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ACVRL1 (ALK1) encodes a TGF-β superfamily type I receptor that acts cell-autonomously in arterial endothelium to restrain endothelial cell proliferation and maintain vascular patterning, with its loss producing dilated vessels and arteriovenous malformations [#0, #2]. ALK1 functions as the specific signaling receptor for BMP9 (and the circulating ligand BMP10), driving phosphorylation of SMAD1/5/8 within a heteromeric BMP type I receptor complex [#1, #14, #8]. Through this axis ALK1 sustains arterial identity (Jag1), supports endoglin (ENG) expression, and limits endothelial proliferation; ENG and ALK1 co-act in distal vessels to promote SMAD1/5/8 activity [#2, #15]. ALK1 signaling is essential for developmental angiogenesis, exemplified by FOXF1/FLI1-driven activation of the BMP9/ACVRL1/SMAD1 pathway in neonatal lung angiogenesis and alveolarization, where exogenous BMP9 rescues ACVRL1-deficient phenotypes [#5]. ACVRL1 transcription is governed by Sp1 acting at GC-rich promoter and intronic elements, repressed by CpG methylation and the E3 ligase EDD, and reinforced by a flow-dependent positive feedback loop in which ligand-activated ALK1 downstream of blood flow maintains its own expression [#4, #9, #10, #14]. Heterozygous loss-of-function causes hereditary hemorrhagic telangiectasia type 2 (HHT2) through haploinsufficiency, with disease-associated mutations abolishing BMP9-stimulated signaling or undergoing NMD-mediated degradation, while somatic second-hit mutations in trans produce Knudsonian bi-allelic loss in telangiectasia lesions; ACVRL1 mutations also cause pulmonary arterial hypertension and vein of Galen aneurysmal malformation by impairing BMP9/ALK1 signaling [#1, #6, #7, #11, #12, #13].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established the cellular role of Acvrl1 in vivo, showing it normally restrains endothelial cell proliferation in arterial endothelium rather than acting only as a generic signaling component.\",\n      \"evidence\": \"Zebrafish forward genetic screen and positional cloning of violet beauregarde loss-of-function mutants\",\n      \"pmids\": [\"12050147\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the activating ligand or downstream SMAD effectors\", \"Mechanism linking proliferation control to vessel patterning unresolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstrated that haploinsufficiency of Acvrl1 is sufficient to recapitulate HHT2, establishing dosage sensitivity as the disease mechanism in a mammalian system.\",\n      \"evidence\": \"Acvrl1+/- heterozygous mouse model with systematic multi-organ histopathology\",\n      \"pmids\": [\"12588795\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not explain age-dependence or tissue specificity of lesions\", \"Molecular events downstream of reduced dosage not defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Linked Eng and Acvrl1 spatially, showing co-expression in distal vessels and Eng-dependent maintenance of pSmad1/5/8, framing endoglin as a partner in ALK1-mediated signaling.\",\n      \"evidence\": \"Laser-microdissection RT-PCR and pSmad1/5/8 immunohistochemistry in Eng+/- and wild-type mouse lung\",\n      \"pmids\": [\"19015642\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Correlative co-expression without direct biochemical demonstration of an ENG-ALK1 complex\", \"Single lab, limited to lung vasculature\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Used Drosophila genetics to place the ALK1 ortholog within a heteromeric BMP receptor complex and to show that HHT2-equivalent substitutions can confer gain-of-function in that context.\",\n      \"evidence\": \"Generation and epistasis analysis of 15 saxophone alleles with comparison to human ACVRL1 mutations\",\n      \"pmids\": [\"19620392\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"sax is ortholog of both ALK1 and ALK2, complicating direct assignment\", \"Gain-of-function inference not confirmed for human ALK1 in mammalian cells\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified BMP9 as the specific activating ligand and systematically established loss-of-function/haploinsufficiency as the mechanism, while ruling out dominant-negative action of HHT2 mutants.\",\n      \"evidence\": \"Transfection of 19 HHT2 ALK1 mutants with BMP9 binding, SMAD signaling, and dominant-negative assays\",\n      \"pmids\": [\"20501893\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address in vivo ligand availability or BMP10 contribution\", \"Receptor complex stoichiometry not resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined the transcriptional control of ACVRL1, showing Sp1 binding to GC-rich promoter elements drives expression and that CpG methylation silences it.\",\n      \"evidence\": \"5'RACE, Sp1-titration and siRNA luciferase reporter assays, ChIP, and in vitro promoter methylation\",\n      \"pmids\": [\"20587022\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not connect Sp1 regulation to endothelial-specific or flow-responsive expression\", \"Upstream signals controlling Sp1 activity at this promoter unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended ACVRL1 regulation to an intronic Sp1-dependent element, showing a disease-associated intron 6 variant reduces expression by abolishing Sp1 binding.\",\n      \"evidence\": \"Patient-sample RT-PCR/immunoblot, luciferase reporter, and Sp1 EMSA\",\n      \"pmids\": [\"23460919\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single variant in a single lab\", \"Quantitative contribution of the intronic element to total expression unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified EDD as a negative transcriptional regulator of ACVRL1, adding a brake on expression whose loss deregulates SMAD signaling and vessel development.\",\n      \"evidence\": \"ChIP-chip/expression profiling integration with EDD siRNA knockdown and endothelial motility assays\",\n      \"pmids\": [\"24189493\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which EDD represses the promoter not detailed\", \"Single lab without independent confirmation\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealed a glucocorticoid-driven switch, via Tgfbr3 upregulation, that diverts TGF-β signaling into the Acvrl1/Smad1/5/8 axis to promote myofibroblast differentiation.\",\n      \"evidence\": \"Pharmacological and siRNA Tgfbr3 knockdown studies across multiple cell types with in vivo dexamethasone and phospho-Smad readouts\",\n      \"pmids\": [\"24347165\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relevance to endothelial/vascular ALK1 function not established\", \"Direct interaction between Tgfbr3 and ALK1 not biochemically mapped\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected ALK1 dysfunction to vein of Galen aneurysmal malformation by showing an extracellular-domain variant abolishes BMP9-stimulated SMAD1/5/8 phosphorylation.\",\n      \"evidence\": \"pSMAD1/5/8 immunoblotting and transcriptional reporter assays for wild-type versus R218W ALK1 after BMP9 stimulation\",\n      \"pmids\": [\"27625857\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single mutant in a single patient context\", \"Causality at the organismal level not demonstrated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established the endothelial-cell-autonomous in vivo mechanism, placing Jag1 (arterial identity), endoglin expression, and proliferation control downstream of Acvrl1/Smad1/5/8.\",\n      \"evidence\": \"Conditional endothelial-specific Acvrl1 knockout mice with retinal angiogenesis, pSmad1/5/8, Jag1, and Eng readouts\",\n      \"pmids\": [\"24896812\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define how SMAD targets coordinate arterial identity with proliferation\", \"Direct transcriptional targets of the pathway not mapped\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Consolidated the haploinsufficiency mechanism across many mutations, showing both loss of receptor signaling activity and splicing/NMD-mediated allele loss.\",\n      \"evidence\": \"BMP9 signaling, protein maturation/localization, and minigene splicing assays of 23 ACVRL1 mutations\",\n      \"pmids\": [\"26176610\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address modifiers explaining variable HHT2 expressivity\", \"In vivo consequences of NMD alleles not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Broadened the disease spectrum by showing PAH-associated ACVRL1 missense mutations impair BMP9/ALK1 SMAD1/5 signaling.\",\n      \"evidence\": \"BMP9-stimulated phospho-Smad1/5 immunoblot and luciferase reporter assays of four PAH mutants in NIH-3T3 cells\",\n      \"pmids\": [\"27316748\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vitro overexpression system, single lab\", \"Vascular-bed-specific basis of PAH versus HHT phenotypes unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified non-coding intron 9 as a functionally important splicing-regulatory region, explaining HHT in coding-mutation-negative families.\",\n      \"evidence\": \"Whole genome sequencing and RNA splicing analysis across multiple unrelated families\",\n      \"pmids\": [\"30244195\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Precise cis-elements and trans-factors within the hotspot not defined\", \"Single lab cohort\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Refined the disease model from simple haploinsufficiency to a Knudsonian two-hit mechanism, demonstrating somatic second-hit mutations in trans within telangiectasia lesions.\",\n      \"evidence\": \"Next-generation sequencing of telangiectasia tissue with allele phasing of germline and somatic mutations\",\n      \"pmids\": [\"31630786\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why focal bi-allelic loss occurs at specific sites unknown\", \"Reconciliation with germline haploinsufficiency models incomplete\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Positioned ACVRL1 in a developmental transcriptional circuit, showing FOXF1/FLI1 activate the BMP9/ACVRL1/SMAD1 pathway to drive neonatal lung angiogenesis with BMP9 rescue.\",\n      \"evidence\": \"scRNA-seq, nanoparticle ACVRL1 silencing in newborn mice, FOXF1/FLI1 promoter assays, and BMP9 rescue\",\n      \"pmids\": [\"35440116\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct FOXF1/FLI1 binding sites on the ACVRL1 promoter not finely mapped\", \"Generalizability beyond neonatal lung not addressed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Uncovered a non-canonical, SMAD-independent ACVRL1 function in cancer, where it scaffolds USP15-mediated deubiquitination of GPX2 to confer tyrosine kinase inhibitor resistance.\",\n      \"evidence\": \"LC-MS, Co-IP, truncation mapping, ubiquitination assays, and CRISPR GPX2 lysine-mutant rescue in colorectal cancer models\",\n      \"pmids\": [\"37743483\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; reciprocal validation of the ACVRL1-GPX2-USP15 interactions limited\", \"Relationship to canonical receptor signaling unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a flow-driven positive feedback loop in which ligand (BMP10/BMP9)-dependent ALK1 activity downstream of blood flow maintains acvrl1 transcription.\",\n      \"evidence\": \"Zebrafish flow manipulation, acvrl1:egfp reporter, bmp10 mutants, intravascular BMP9/BMP10 rescue, and human endothelial shear-stress assays\",\n      \"pmids\": [\"38727966\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcription factors transducing the flow/ALK1 signal to the promoter not identified\", \"Quantitative dynamics of the feedback loop not modeled\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ALK1/SMAD1/5/8 output is converted into specific transcriptional programs controlling arterial identity, proliferation, and lesion formation, and which downstream effectors integrate flow, ligand, and ENG inputs, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct SMAD target genes coordinating arterial identity and proliferation not mapped\", \"Mechanism reconciling haploinsufficiency with focal two-hit lesion formation incomplete\", \"Structural basis of BMP9/BMP10-ALK1-ENG complex assembly not defined in the corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 2, 11]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [1, 14]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2, 14]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 2, 5]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [4, 9, 10]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [6, 7, 11, 12]}\n    ],\n    \"complexes\": [\"BMP type I receptor complex\"],\n    \"partners\": [\"BMP9\", \"BMP10\", \"ENG\", \"TGFBR3\", \"USP15\", \"GPX2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}