Affinage

Showing ACVRL1 — ALK1 is a alias.

ACVRL1

Activin receptor type-1-like · UniProt P37023

Length
503 aa
Mass
56.1 kDa
Annotated
2026-06-09
100 papers in source corpus 18 papers cited in narrative 18 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2002 High

    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

    PMID:12050147

    Open questions at the time
    • Did not identify the activating ligand or downstream SMAD effectors
    • Mechanism linking proliferation control to vessel patterning unresolved
  2. 2003 High

    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

    PMID:12588795

    Open questions at the time
    • Did not explain age-dependence or tissue specificity of lesions
    • Molecular events downstream of reduced dosage not defined
  3. 2008 Medium

    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

    PMID:19015642

    Open questions at the time
    • Correlative co-expression without direct biochemical demonstration of an ENG-ALK1 complex
    • Single lab, limited to lung vasculature
  4. 2009 Medium

    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

    PMID:19620392

    Open questions at the time
    • sax is ortholog of both ALK1 and ALK2, complicating direct assignment
    • Gain-of-function inference not confirmed for human ALK1 in mammalian cells
  5. 2010 High

    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

    PMID:20501893

    Open questions at the time
    • Did not address in vivo ligand availability or BMP10 contribution
    • Receptor complex stoichiometry not resolved
  6. 2010 High

    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

    PMID:20587022

    Open questions at the time
    • Did not connect Sp1 regulation to endothelial-specific or flow-responsive expression
    • Upstream signals controlling Sp1 activity at this promoter unknown
  7. 2013 Medium

    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

    PMID:23460919

    Open questions at the time
    • Single variant in a single lab
    • Quantitative contribution of the intronic element to total expression unclear
  8. 2013 Medium

    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

    PMID:24189493

    Open questions at the time
    • Mechanism by which EDD represses the promoter not detailed
    • Single lab without independent confirmation
  9. 2013 High

    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

    PMID:24347165

    Open questions at the time
    • Relevance to endothelial/vascular ALK1 function not established
    • Direct interaction between Tgfbr3 and ALK1 not biochemically mapped
  10. 2013 Medium

    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

    PMID:27625857

    Open questions at the time
    • Single mutant in a single patient context
    • Causality at the organismal level not demonstrated
  11. 2014 High

    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

    PMID:24896812

    Open questions at the time
    • Did not define how SMAD targets coordinate arterial identity with proliferation
    • Direct transcriptional targets of the pathway not mapped
  12. 2015 High

    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

    PMID:26176610

    Open questions at the time
    • Did not address modifiers explaining variable HHT2 expressivity
    • In vivo consequences of NMD alleles not tested
  13. 2016 Medium

    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

    PMID:27316748

    Open questions at the time
    • In vitro overexpression system, single lab
    • Vascular-bed-specific basis of PAH versus HHT phenotypes unresolved
  14. 2018 Medium

    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

    PMID:30244195

    Open questions at the time
    • Precise cis-elements and trans-factors within the hotspot not defined
    • Single lab cohort
  15. 2019 High

    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

    PMID:31630786

    Open questions at the time
    • Why focal bi-allelic loss occurs at specific sites unknown
    • Reconciliation with germline haploinsufficiency models incomplete
  16. 2022 High

    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

    PMID:35440116

    Open questions at the time
    • Direct FOXF1/FLI1 binding sites on the ACVRL1 promoter not finely mapped
    • Generalizability beyond neonatal lung not addressed
  17. 2023 Medium

    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

    PMID:37743483

    Open questions at the time
    • Single lab; reciprocal validation of the ACVRL1-GPX2-USP15 interactions limited
    • Relationship to canonical receptor signaling unclear
  18. 2024 High

    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

    PMID:38727966

    Open questions at the time
    • Transcription factors transducing the flow/ALK1 signal to the promoter not identified
    • Quantitative dynamics of the feedback loop not modeled

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 3 GO:0016740 transferase activity 2 GO:0060089 molecular transducer activity 2
Localization
GO:0005886 plasma membrane 2
Pathway
R-HSA-1643685 Disease 4 R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3 R-HSA-74160 Gene expression (Transcription) 3
Partners
BMP10BMP9ENGGPX2TGFBR3USP15
Complex memberships
BMP type I receptor complex

Evidence

Reading pass · 18 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 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. Zebrafish forward genetic screen; positional cloning; loss-of-function mutant phenotypic analysis Development (Cambridge, England) High 12050147
2010 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. Cell transfection with 19 HHT2-associated ALK1 mutants; BMP9 binding assays; BMP9-stimulated SMAD signaling assays; dominant-negative functional testing Blood High 20501893
2014 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. 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 PloS one High 24896812
2013 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. 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 The Journal of biological chemistry High 24347165
2010 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. 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 BMC molecular biology High 20587022
2022 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. 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) Nature communications High 35440116
2019 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. Next-generation sequencing of telangiectasia tissue; allele phasing of somatic and germline mutations American journal of human genetics High 31630786
2003 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. Acvrl1+/- heterozygous mouse model; histopathology; fecal occult blood testing; systematic organ examination Human molecular genetics High 12588795
2009 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. Drosophila genetics; generation and characterization of 15 sax alleles; epistasis analysis with BMP pathway components; reversion genetics; amino acid comparison with human ACVRL1 mutations Genetics Medium 19620392
2013 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. 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 Biochimica et biophysica acta Medium 24189493
2013 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. RT-PCR and immunoblot quantification in patient-derived samples; luciferase reporter assay; electrophoretic mobility shift assay (EMSA) with Sp1 PloS one Medium 23460919
2015 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. BMP9-stimulated SMAD signaling assays; Western blot for protein maturation; fluorescence microscopy for protein localization; minigene splicing assay PloS one High 26176610
2016 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. Transfection of ACVRL1 mutants into NIH-3T3 cells; BMP9 stimulation; phospho-Smad1/5 immunoblot; luciferase BMP reporter assay Clinical science (London, England : 1979) Medium 27316748
2013 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. Immunoblotting for pSMAD1/5/8 after BMP9 stimulation in cells transfected with wild-type or mutant ACVRL1; transcriptional activation reporter assay Journal of pediatric genetics Medium 27625857
2024 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. Zebrafish flow manipulation experiments; acvrl1:egfp transgenic reporter line; bmp10 mutant zebrafish; intravascular BMP9/BMP10 injection; human endothelial cell shear stress assay; RT-qPCR Angiogenesis High 38727966
2008 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. Immunohistochemistry; RT-PCR from laser-microdissected pulmonary arterial, venous, and capillary segments; pSmad1/5/8 immunostaining in Eng+/- and wild-type mice Laboratory investigation; a journal of technical methods and pathology Medium 19015642
2023 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. 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 BMC medicine Medium 37743483
2018 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. Whole genome sequencing; next-generation sequencing panel capturing coding and non-coding regions; RNA splicing analysis Journal of medical genetics Medium 30244195

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Disruption of acvrl1 increases endothelial cell number in zebrafish cranial vessels. Development (Cambridge, England) 310 12050147
2010 Clinical outcomes of pulmonary arterial hypertension in patients carrying an ACVRL1 (ALK1) mutation. American journal of respiratory and critical care medicine 231 20056902
2006 SMAD4 mutations found in unselected HHT patients. Journal of medical genetics 187 16613914
2007 Genotype-phenotype correlations in hereditary hemorrhagic telangiectasia: data from the French-Italian HHT network. Genetics in medicine : official journal of the American College of Medical Genetics 171 17224686
2003 A mouse model for hereditary hemorrhagic telangiectasia (HHT) type 2. Human molecular genetics 149 12588795
2010 Overlapping spectra of SMAD4 mutations in juvenile polyposis (JP) and JP-HHT syndrome. American journal of medical genetics. Part A 121 20101697
2014 Endothelial depletion of Acvrl1 in mice leads to arteriovenous malformations associated with reduced endoglin expression. PloS one 116 24896812
2006 Novel mutations in ENG and ACVRL1 identified in a series of 200 individuals undergoing clinical genetic testing for hereditary hemorrhagic telangiectasia (HHT): correlation of genotype with phenotype. Human mutation 115 16752392
2019 Somatic Mutations in Vascular Malformations of Hereditary Hemorrhagic Telangiectasia Result in Bi-allelic Loss of ENG or ACVRL1. American journal of human genetics 110 31630786
2004 Molecular screening of ALK1/ACVRL1 and ENG genes in hereditary hemorrhagic telangiectasia in France. Human mutation 96 15024723
2010 Functional analysis of the BMP9 response of ALK1 mutants from HHT2 patients: a diagnostic tool for novel ACVRL1 mutations. Blood 72 20501893
2000 Clinical manifestations in a large hereditary hemorrhagic telangiectasia (HHT) type 2 kindred. American journal of medical genetics 69 10946360
2006 Distribution of ENG and ACVRL1 (ALK1) mutations in French HHT patients. Human mutation 68 16705692
2010 Estrogen therapy for hereditary haemorrhagic telangiectasia (HHT): Effects of raloxifene, on Endoglin and ALK1 expression in endothelial cells. Thrombosis and haemostasis 67 20135064
2000 A hereditary haemorrhagic telangiectasia family with pulmonary involvement is unlinked to the known HHT genes, endoglin and ALK-1. Thorax 65 10899246
2013 Glucocorticoids recruit Tgfbr3 and Smad1 to shift transforming growth factor-β signaling from the Tgfbr1/Smad2/3 axis to the Acvrl1/Smad1 axis in lung fibroblasts. The Journal of biological chemistry 58 24347165
2007 Analysis of ENG and ACVRL1 genes in 137 HHT Italian families identifies 76 different mutations (24 novel). Comparison with other European studies. Journal of human genetics 56 17786384
2022 Endothelial progenitor cells stimulate neonatal lung angiogenesis through FOXF1-mediated activation of BMP9/ACVRL1 signaling. Nature communications 52 35440116
2017 Quality of life in patients with hereditary haemorrhagic telangiectasia (HHT). Health and quality of life outcomes 52 28114930
2019 Phenotype of CM-AVM2 caused by variants in EPHB4: how much overlap with hereditary hemorrhagic telangiectasia (HHT)? Genetics in medicine : official journal of the American College of Medical Genetics 45 30760892
2009 The effect of N-acetylcysteine on epistaxis and quality of life in patients with HHT: a pilot study. Rhinology 45 19382502
2008 Endoglin and activin receptor-like-kinase 1 are co-expressed in the distal vessels of the lung: implications for two familial vascular dysplasias, HHT and PAH. Laboratory investigation; a journal of technical methods and pathology 42 19015642
2007 Therapeutic action of tranexamic acid in hereditary haemorrhagic telangiectasia (HHT): regulation of ALK-1/endoglin pathway in endothelial cells. Thrombosis and haemostasis 42 17264955
2006 Association of a polymorphism of the ACVRL1 gene with sporadic arteriovenous malformations of the central nervous system. Journal of neurosurgery 41 16776339
2006 Patients with Hereditary Hemorrhagic Telangectasia (HHT) exhibit a deficit of polymorphonuclear cell and monocyte oxidative burst and phagocytosis: a possible correlation with altered adaptive immune responsiveness in HHT. Current pharmaceutical design 40 16611102
2005 High frequency of ENG and ALK1/ACVRL1 mutations in German HHT patients. Human mutation 37 15880681
2020 Current HHT genetic overview in Spain and its phenotypic correlation: data from RiHHTa registry. Orphanet journal of rare diseases 36 32503579
2006 Hereditary Haemorrhagic Telangiectasia (HHT): genetic and molecular aspects. Current pharmaceutical design 36 16611099
2021 Homozygous GDF2 nonsense mutations result in a loss of circulating BMP9 and BMP10 and are associated with either PAH or an "HHT-like" syndrome in children. Molecular genetics & genomic medicine 35 33834622
2014 Novel mutations in BMPR2, ACVRL1 and KCNA5 genes and hemodynamic parameters in patients with pulmonary arterial hypertension. PloS one 35 24936649
2009 Impaired recruitment of HHT-1 mononuclear cells to the ischaemic heart is due to an altered CXCR4/CD26 balance. Cardiovascular research 34 19762327
2015 JP-HHT phenotype in Danish patients with SMAD4 mutations. Clinical genetics 33 26572829
2011 Mosaic ACVRL1 and ENG mutations in hereditary haemorrhagic telangiectasia patients. Journal of medical genetics 32 21378382
2015 Mononuclear cells and vascular repair in HHT. Frontiers in genetics 28 25852751
2010 Characterization of the human Activin-A receptor type II-like kinase 1 (ACVRL1) promoter and its regulation by Sp1. BMC molecular biology 28 20587022
2006 DHPLC-based mutation analysis of ENG and ALK-1 genes in HHT Italian population. Human mutation 28 16429404
2016 20-year follow-up study of Danish HHT patients-survival and causes of death. Orphanet journal of rare diseases 27 27876060
1985 12-L-hydroxy-5,8,10-heptadecatrienoic acid (HHT) is an excellent substrate for NAD+-dependent 15-hydroxyprostaglandin dehydrogenase. Biochemical and biophysical research communications 27 4004878
2010 Reduced plasma levels of Ang-2 and sEng as novel biomarkers in hereditary hemorrhagic telangiectasia (HHT). Clinica chimica acta; international journal of clinical chemistry 26 20067780
2008 Hereditary hemorrhagic telangiectasia: evidence for regional founder effects of ACVRL1 mutations in French and Italian patients. European journal of human genetics : EJHG 26 18285823
2018 Mutations in the ENG, ACVRL1, and SMAD4 genes and clinical manifestations of hereditary haemorrhagic telangiectasia: experience from the Center for Osler's Disease, Uppsala University Hospital. Upsala journal of medical sciences 24 30251589
2006 Mutation analysis in hereditary haemorrhagic telangiectasia in Germany reveals 11 novel ENG and 12 novel ACVRL1/ALK1 mutations. Clinical genetics 24 16542389
2020 Genotype-Phenotype Correlations in Children with HHT. Journal of clinical medicine 22 32842615
2019 A theory for polymicrogyria and brain arteriovenous malformations in HHT. Neurology 22 30584075
2011 ACVRL1 germinal mosaic with two mutant alleles in hereditary hemorrhagic telangiectasia associated with pulmonary arterial hypertension. Clinical genetics 22 21651515
2013 ACVRL1 gene variant in a patient with vein of Galen aneurysmal malformation. Journal of pediatric genetics 20 27625857
2009 Functional analysis of saxophone, the Drosophila gene encoding the BMP type I receptor ortholog of human ALK1/ACVRL1 and ACVR1/ALK2. Genetics 20 19620392
2015 Functional and splicing defect analysis of 23 ACVRL1 mutations in a cohort of patients affected by Hereditary Hemorrhagic Telangiectasia. PloS one 19 26176610
1987 The platelet cyclooxygenase metabolite 12-L-hydroxy-5, 8, 10-hepta-decatrienoic acid (HHT) may modulate primary hemostasis by stimulating prostacyclin production. Prostaglandins 18 3124219
2015 Executive summary of the 11th HHT international scientific conference. Angiogenesis 17 26391603
2003 Substrate specificity of the alpha-L-arabinofuranosidase from Rhizomucor pusillus HHT-1. Carbohydrate research 17 12829392
2024 Mutations causing premature termination codons discriminate and generate cellular and clinical variability in HHT. Blood 16 38457357
2023 ACVRL1 drives resistance to multitarget tyrosine kinase inhibitors in colorectal cancer by promoting USP15-mediated GPX2 stabilization. BMC medicine 16 37743483
2016 Familial occurrence of brain arteriovenous malformation: a novel ACVRL1 mutation detected by whole exome sequencing. Journal of neurosurgery 16 27611203
2015 The ACVRL1 c.314-35A>G polymorphism is associated with organ vascular malformations in hereditary hemorrhagic telangiectasia patients with ENG mutations, but not in patients with ACVRL1 mutations. American journal of medical genetics. Part A 15 25847705
1988 Modulation of human monocyte leukotactic responsiveness by thromboxane A2 and 12-hydroxyheptadecatrienoic acid (12-HHT). Journal of leukocyte biology 15 3422086
2018 Genome sequencing reveals a deep intronic splicing ACVRL1 mutation hotspot in Hereditary Haemorrhagic Telangiectasia. Journal of medical genetics 14 30244195
2017 Characterization of pulmonary arteriovenous malformations in ACVRL1 versus ENG mutation carriers in hereditary hemorrhagic telangiectasia. Genetics in medicine : official journal of the American College of Medical Genetics 14 29048420
2012 Polymorphisms in ACVRL1 and endoglin genes are not associated with sporadic and HHT-related brain AVMs in Dutch patients. Translational stroke research 14 24323303
2008 Detection of a significant association between mutations in the ACVRL1 gene and hepatic involvement in German patients with hereditary haemorrhagic telangiectasia. Clinical genetics 14 18498373
2006 HHT: a rare disease with a broad spectrum of clinical aspects. Current pharmaceutical design 14 16611103
1987 The use of 12-hydroxyheptadecatrienoic acid (HHT) as an HPLC/spectrophotometric marker for cyclooxygenase pathway activity in resident rat peritoneal cells. Prostaglandins, leukotrienes, and medicine 14 3033686
2022 Pulmonary arterial hypertension in hereditary hemorrhagic telangiectasia associated with ACVRL1 mutation: a case report. Journal of medical case reports 13 35232468
2022 Whole genome sequences discriminate hereditary hemorrhagic telangiectasia phenotypes by non-HHT deleterious DNA variation. Blood advances 13 35316832
2024 Investigation of the Genetic Determinants of Telangiectasia and Solid Organ Arteriovenous Malformation Formation in Hereditary Hemorrhagic Telangiectasia (HHT). International journal of molecular sciences 12 39062925
2022 Distribution of Cerebrovascular Phenotypes According to Variants of the ENG and ACVRL1 Genes in Subjects with Hereditary Hemorrhagic Telangiectasia. Journal of clinical medicine 12 35628811
2015 Mutation analysis in Norwegian families with hereditary hemorrhagic telangiectasia: founder mutations in ACVRL1. Clinical genetics 12 25970827
2013 An intron mutation in the ACVRL1 may be associated with a transcriptional regulation defect in a Chinese family with hereditary hemorrhagic telangiectasia. PloS one 12 23460919
2006 Novel mutations in the ENG and ACVRL1 genes causing hereditary hemorrhagic teleangiectasia. International journal of molecular medicine 12 16525724
2023 Executive summary of the 14th HHT international scientific conference. Angiogenesis 11 37695357
2020 Structure of the agonist 12-HHT in its BLT2 receptor-bound state. Scientific reports 11 32060341
2019 Pulmonary Hypertension and Hereditary Hemorrhagic Telangiectasia Related to an ACVRL1 Mutation. Internal medicine (Tokyo, Japan) 11 31511490
2017 Whole-exome sequencing identifies SGCD and ACVRL1 mutations associated with total anomalous pulmonary venous return (TAPVR) in Chinese population. Oncotarget 11 28412737
2013 A functional genomic approach reveals the transcriptional role of EDD in the expression and function of angiogenesis regulator ACVRL1. Biochimica et biophysica acta 11 24189493
2006 HHT in childhood: screening for special patients. Current pharmaceutical design 11 16611104
2022 Hsa_circ_0129047 regulates the miR-375/ACVRL1 axis to attenuate the progression of lung adenocarcinoma. Journal of clinical laboratory analysis 10 35908770
2020 An ACVRL1 gene mutation presenting as vein of Galen malformation at prenatal diagnosis. American journal of medical genetics. Part A 10 32170914
2010 Fine mapping of the hereditary haemorrhagic telangiectasia (HHT)3 locus on chromosome 5 excludes VE-Cadherin-2, Sprouty4 and other interval genes. Journal of angiogenesis research 10 20701797
2023 Functional filter for whole-genome sequencing data identifies HHT and stress-associated non-coding SMAD4 polyadenylation site variants >5 kb from coding DNA. American journal of human genetics 9 37816352
2020 Generation and genetic repair of 2 iPSC clones from a patient bearing a heterozygous c.1120del18 mutation in the ACVRL1 gene leading to Hereditary Hemorrhagic Telangiectasia (HHT) type 2. Stem cell research 9 32485642
2008 Studies on membrane-associated prostaglandin E synthase-2 with reference to production of 12L-hydroxy-5,8,10-heptadecatrienoic acid (HHT). Biochemical and biophysical research communications 9 18198127
2025 Arteriovenous malformation from a patient with JP-HHT harbours two second-hit somatic DNA alterations in SMAD4. Journal of medical genetics 8 39939156
2024 Blood flow regulates acvrl1 transcription via ligand-dependent Alk1 activity. Angiogenesis 8 38727966
2020 Analysis of the Complete Genome of the Alkaliphilic and Phototrophic Firmicute Heliorestis convoluta Strain HHT. Microorganisms 8 32106460
2018 Executive summary of the 12th HHT international scientific conference. Angiogenesis 8 29147802
2009 Clinical features and mutations in the ENG, ACVRL1, and SMAD4 genes in Korean patients with hereditary hemorrhagic telangiectasia. Journal of Korean medical science 8 19270816
2005 Hereditary hemorrhagic telangiectasia is caused by the Q490X mutation of the ACVRL1 gene in a large Arab family: support of homozygous lethality. European journal of medical genetics 8 16829353
2020 Sequence variations of ACVRL1 play a critical role in hepatic vascular malformations in hereditary hemorrhagic telangiectasia. Orphanet journal of rare diseases 7 32962750
2019 Topically Applied Etamsylate: A New Orphan Drug for HHT-Derived Epistaxis (Antiangiogenesis through FGF Pathway Inhibition). TH open : companion journal to thrombosis and haemostasis 7 31360828
2018 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. Journal of Alzheimer's disease : JAD 7 29843236
2016 Identification of multiple ACVRL1 mutations in patients with pulmonary arterial hypertension by targeted exome capture. Clinical science (London, England : 1979) 7 27316748
2025 Hereditary Hemorrhagic Telangiectasia Prevalence Estimates Calculated From GnomAD Allele Frequencies of Predicted Pathogenic Variants in ENG and ACVRL1. Circulation. Genomic and precision medicine 6 40964703
2024 Specifications of the ACMG/AMP Variant Curation Guidelines for Hereditary Hemorrhagic Telangiectasia Genes-ENG and ACVRL1. Human mutation 6 40225928
2023 Generation of a Syngeneic Heterozygous ACVRL1 Knockout iPS Cell Line for the In Vitro Study of HHT2-Associated Angiogenesis. Cells 5 37371070
2022 Characterization of the Newly Established Homoharringtonine- (HHT-) Resistant Cell Lines and Mechanisms of Resistance. Journal of oncology 5 36081671
2021 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. Biochemical pharmacology 5 34161796
2019 The 12-HHT/BLT2/NO Axis Is Associated to the Wound Healing and Skin Condition in Different Glycaemic States. Medical sciences (Basel, Switzerland) 5 31022982
2018 Functional analysis of a novel ENG variant in a patient with hereditary hemorrhagic telangiectasia (HHT) identifies a new Sp1 binding-site. Gene 5 29305977
2015 Metformin as possible therapy of pulmonary arterio venous malformation in HHT patients. Medical hypotheses 5 25981877
1991 Purification and characterization of dipeptidyl peptidase IV from Streptococcus salivarius HHT. Microbios 5 1684633

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