{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T03:12:10Z","timestamp":1793416330064,"version":"4.5.0"},"reference-count":62,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2023,7,29]],"date-time":"2023-07-29T00:00:00Z","timestamp":1690588800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Grants-in-Aid for Scientific Research","award":["JP21H02890"],"award-info":[{"award-number":["JP21H02890"]}]},{"name":"Grants-in-Aid for Scientific Research","award":["JP20K08272"],"award-info":[{"award-number":["JP20K08272"]}]},{"name":"Grants-in-Aid for Scientific Research","award":["JP22K06803"],"award-info":[{"award-number":["JP22K06803"]}]},{"name":"Grants-in-Aid for Scientific Research","award":["JP21K20928"],"award-info":[{"award-number":["JP21K20928"]}]},{"name":"Grants-in-Aid for Scientific Research","award":["JP22K16123"],"award-info":[{"award-number":["JP22K16123"]}]},{"name":"Grants-in-Aid for Scientific Research","award":["JP21K20751"],"award-info":[{"award-number":["JP21K20751"]}]},{"name":"Grants-in-Aid for Scientific Research","award":["JP22K15361"],"award-info":[{"award-number":["JP22K15361"]}]},{"name":"Grants-in-Aid for Scientific Research","award":["21-2-6"],"award-info":[{"award-number":["21-2-6"]}]},{"name":"Smoking Research Foundation","award":["JP21H02890"],"award-info":[{"award-number":["JP21H02890"]}]},{"name":"Smoking Research Foundation","award":["JP20K08272"],"award-info":[{"award-number":["JP20K08272"]}]},{"name":"Smoking Research Foundation","award":["JP22K06803"],"award-info":[{"award-number":["JP22K06803"]}]},{"name":"Smoking Research Foundation","award":["JP21K20928"],"award-info":[{"award-number":["JP21K20928"]}]},{"name":"Smoking Research Foundation","award":["JP22K16123"],"award-info":[{"award-number":["JP22K16123"]}]},{"name":"Smoking Research Foundation","award":["JP21K20751"],"award-info":[{"award-number":["JP21K20751"]}]},{"name":"Smoking Research Foundation","award":["JP22K15361"],"award-info":[{"award-number":["JP22K15361"]}]},{"name":"Smoking Research Foundation","award":["21-2-6"],"award-info":[{"award-number":["21-2-6"]}]},{"name":"Intramural Research Fund for Cardiovascular Diseases of National Cerebral and Cardiovascular Center","award":["JP21H02890"],"award-info":[{"award-number":["JP21H02890"]}]},{"name":"Intramural Research Fund for Cardiovascular Diseases of National Cerebral and Cardiovascular Center","award":["JP20K08272"],"award-info":[{"award-number":["JP20K08272"]}]},{"name":"Intramural Research Fund for Cardiovascular Diseases of National Cerebral and Cardiovascular Center","award":["JP22K06803"],"award-info":[{"award-number":["JP22K06803"]}]},{"name":"Intramural Research Fund for Cardiovascular Diseases of National Cerebral and Cardiovascular Center","award":["JP21K20928"],"award-info":[{"award-number":["JP21K20928"]}]},{"name":"Intramural Research Fund for Cardiovascular Diseases of National Cerebral and Cardiovascular Center","award":["JP22K16123"],"award-info":[{"award-number":["JP22K16123"]}]},{"name":"Intramural Research Fund for Cardiovascular Diseases of National Cerebral and Cardiovascular Center","award":["JP21K20751"],"award-info":[{"award-number":["JP21K20751"]}]},{"name":"Intramural Research Fund for Cardiovascular Diseases of National Cerebral and Cardiovascular Center","award":["JP22K15361"],"award-info":[{"award-number":["JP22K15361"]}]},{"name":"Intramural Research Fund for Cardiovascular Diseases of National Cerebral and Cardiovascular Center","award":["21-2-6"],"award-info":[{"award-number":["21-2-6"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Hereditary hemorrhagic telangiectasia (HHT) is a vascular disease caused by the defects of ALK1\/ACVRL1 receptor signaling. In this study, we evaluated 25 recently identified ACVRL1 missense variants using multiple computational pathogenicity classifiers and experimentally characterized their signal transduction capacity. Three extracellular residue variants showed no detectable cell surface expression and impairment of bone morphogenetic protein 9 (BMP9) responsiveness of SMAD-dependent transcription in luciferase assays. Four variants with amino acid replacement in the motifs essential for the intracellular kinase function lost SMAD-dependent signaling. Most of other variations in the kinase domain also caused marked downregulation of signaling; however, two variants behaved as the wild-type ACVRL1 did, while computational classifiers predicted their functional abnormalities. Three-dimensional structure prediction using the ColabFold program supported the significance of the L45 loop and NANDOR domain of ACVRL1 for its association with SMAD1 and BMPR2, respectively, and the variations in these motifs resulted in the reduction of SMAD signaling. On the other hand, two of the GS domain variants maintained high signal transduction capacity, which did not accord with their computational pathogenicity prediction. These results affirm the requirement of a combinatory approach using computational and experimental analyses to accurately predict the pathogenicity of ACVRL1 missense variants in the HHT patients.<\/jats:p>","DOI":"10.3390\/jcm12155002","type":"journal-article","created":{"date-parts":[[2023,7,31]],"date-time":"2023-07-31T02:13:32Z","timestamp":1690769612000},"page":"5002","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Computational and Experimental Analyses for Pathogenicity Prediction of ACVRL1 Missense Variants in Hereditary Hemorrhagic Telangiectasia"],"prefix":"10.3390","volume":"12","author":[{"given":"Toru","family":"Iwasa","sequence":"first","affiliation":[{"name":"Department of Molecular Physiology, National Cerebral and Cardiovascular Center Research Institute, 6-1 Kishibe-Shimmachi, Suita, Osaka 564-8565, Japan"},{"name":"Department of Pediatric Cardiology, National Cerebral and Cardiovascular Center, 6-1 Kishibe-Shimmachi, Suita, Osaka 564-8565, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihiro","family":"Urasaki","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology, National Cerebral and Cardiovascular Center Research Institute, 6-1 Kishibe-Shimmachi, Suita, Osaka 564-8565, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Kakihana","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology, National Cerebral and Cardiovascular Center Research Institute, 6-1 Kishibe-Shimmachi, Suita, Osaka 564-8565, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nami","family":"Nagata-Akaho","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology, National Cerebral and Cardiovascular Center Research Institute, 6-1 Kishibe-Shimmachi, Suita, Osaka 564-8565, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukihiro","family":"Harada","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology, National Cerebral and Cardiovascular Center Research Institute, 6-1 Kishibe-Shimmachi, Suita, Osaka 564-8565, Japan"},{"name":"Laboratory of Stem Cell and Regenerative Medicine, Department of Biomedical Sciences, College of Life Sciences, Ritsumeikan University, 1-1-1 Noji-Higashi, Kusatsu, Shiga 525-8577, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soichi","family":"Takeda","sequence":"additional","affiliation":[{"name":"Department of Advanced Medical Technologies, National Cerebral and Cardiovascular Center Research Institute, 6-1 Kishibe-Shimmachi, Suita, Osaka 564-8565, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teruhisa","family":"Kawamura","sequence":"additional","affiliation":[{"name":"Laboratory of Stem Cell and Regenerative Medicine, Department of Biomedical Sciences, College of Life Sciences, Ritsumeikan University, 1-1-1 Noji-Higashi, Kusatsu, Shiga 525-8577, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4801-7955","authenticated-orcid":false,"given":"Isao","family":"Shiraishi","sequence":"additional","affiliation":[{"name":"Department of Pediatric Cardiology, National Cerebral and Cardiovascular Center, 6-1 Kishibe-Shimmachi, Suita, Osaka 564-8565, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenichi","family":"Kurosaki","sequence":"additional","affiliation":[{"name":"Department of Pediatric Cardiology, National Cerebral and Cardiovascular Center, 6-1 Kishibe-Shimmachi, Suita, Osaka 564-8565, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6956-6374","authenticated-orcid":false,"given":"Hiroko","family":"Morisaki","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Sakakibara Heart Institute, 3-16-1 Asahi-cho, Fuchu, Tokyo 183-0003, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Osamu","family":"Yamada","sequence":"additional","affiliation":[{"name":"Department of Pediatric Cardiology, National Cerebral and Cardiovascular Center, 6-1 Kishibe-Shimmachi, Suita, Osaka 564-8565, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Osamu","family":"Nakagawa","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology, National Cerebral and Cardiovascular Center Research Institute, 6-1 Kishibe-Shimmachi, Suita, Osaka 564-8565, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1002\/(SICI)1096-8628(20000306)91:1<66::AID-AJMG12>3.0.CO;2-P","article-title":"Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome)","volume":"91","author":"Shovlin","year":"2000","journal-title":"Am. J. Med. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Bernabeu, C., Bayrak-Toydemir, P., McDonald, J., and Letarte, M. (2020). Potential Second-Hits in Hereditary Hemorrhagic Telangiectasia. J. Clin. Med., 9.","DOI":"10.3390\/jcm9113571"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/s13023-019-1281-4","article-title":"Future treatments for hereditary hemorrhagic telangiectasia","volume":"15","author":"Robert","year":"2020","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2626","DOI":"10.1073\/pnas.97.6.2626","article-title":"Activin receptor-like kinase 1 modulates transforming growth factor-beta 1 signaling in the regulation of angiogenesis","volume":"97","author":"Oh","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1038\/81634","article-title":"Arteriovenous malformations in mice lacking activin receptor-like kinase-1","volume":"26","author":"Urness","year":"2000","journal-title":"Nat. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3009","DOI":"10.1242\/dev.129.12.3009","article-title":"Disruption of acvrl1 increases endothelial cell number in zebrafish cranial vessels","volume":"129","author":"Roman","year":"2002","journal-title":"Development"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1604","DOI":"10.1182\/blood-2010-03-276881","article-title":"Functional analysis of the BMP9 response of ALK1 mutants from HHT2 patients: A diagnostic tool for novel ACVRL1 mutations","volume":"116","author":"Ricard","year":"2010","journal-title":"Blood"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Alaa El Din, F., Patri, S., Thoreau, V., Rodriguez-Ballesteros, M., Hamade, E., Bailly, S., Gilbert-Dussardier, B., Abou Merhi, R., and Kitzis, A. (2015). Functional and splicing defect analysis of 23 ACVRL1 mutations in a cohort of patients affected by Hereditary Hemorrhagic Telangiectasia. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0132111"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1007\/s11010-012-1496-3","article-title":"Retention in the endoplasmic reticulum is the underlying mechanism of some hereditary haemorrhagic telangiectasia type 2 ALK1 missense mutations","volume":"373","author":"Hume","year":"2013","journal-title":"Mol. Cell Biochem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1101\/gr.176601","article-title":"Predicting deleterious amino acid substitutions","volume":"11","author":"Ng","year":"2001","journal-title":"Genome Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2745","DOI":"10.1093\/bioinformatics\/btv195","article-title":"PROVEAN web server: A tool to predict the functional effect of amino acid substitutions and indels","volume":"31","author":"Choi","year":"2015","journal-title":"Bioinformatics"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1038\/nmeth0410-248","article-title":"A method and server for predicting damaging missense mutations","volume":"7","author":"Adzhubei","year":"2010","journal-title":"Nat. Methods"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2230","DOI":"10.1093\/bioinformatics\/btw222","article-title":"PANTHER-PSEP: Predicting disease-causing genetic variants using position-specific evolutionary preservation","volume":"32","author":"Tang","year":"2016","journal-title":"Bioinformatics"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4883","DOI":"10.1074\/jbc.M111023200","article-title":"Identification and Functional Characterization of Distinct Critically Important Bone Morphogenetic Protein-specific Response Elements in the Id1 Promoter","volume":"277","author":"Korchynskyi","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"8712","DOI":"10.1093\/nar\/gkr572","article-title":"ChIP-seq reveals cell type-specific binding patterns of BMP-specific Smads and a novel binding motif","volume":"39","author":"Morikawa","year":"2011","journal-title":"Nucleic Acids Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"18551","DOI":"10.1074\/jbc.M111.338103","article-title":"Anti-human activin receptor-like kinase 1 (ALK1) antibody attenuates bone morphogenetic protein 9 (BMP9)-induced ALK1 signaling and interferes with endothelial cell sprouting","volume":"287","author":"Thorikay","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1038\/s41592-022-01488-1","article-title":"ColabFold: Making protein folding accessible to all","volume":"19","author":"Mirdita","year":"2022","journal-title":"Nat. Methods"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1038\/jhg.2013.113","article-title":"Hereditary hemorrhagic telangiectasia in Japanese patients","volume":"59","author":"Komiyama","year":"2014","journal-title":"J. Hum. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Kitayama, K., Ishiguro, T., Komiyama, M., Morisaki, T., Morisaki, H., Minase, G., Hamanaka, K., Miyatake, S., Matsumoto, N., and Kato, M. (2021). Mutational and clinical spectrum of Japanese patients with hereditary hemorrhagic telangiectasia. BMC Med. Genom., 14.","DOI":"10.1186\/s12920-021-01139-y"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1111\/ncn3.102","article-title":"Japanese case of hereditary hemorrhagic telangiectasia type 2 with a novel mutation, c.154A>C (p.Thr52Pro), in the ALK1\/ACVRL1 gene","volume":"2","author":"Nishimoto","year":"2014","journal-title":"Neurol. Clin. Neurosci."},{"key":"ref_22","first-page":"9","article-title":"A Case of Spontaneously Improved Heritable Pulmonary Arterial Hypertension Diagnosed as Severe Primary Pulmonary Hypertension in Childhood","volume":"4","author":"Iwasa","year":"2020","journal-title":"J. Pediatr. Cardiol. Card. Surg."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"D980","DOI":"10.1093\/nar\/gkt1113","article-title":"ClinVar: Public archive of relationships among sequence variation and human phenotype","volume":"42","author":"Landrum","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"ref_24","first-page":"655","article-title":"Novel mutations in the ENG and ACVRL1 genes causing hereditary hemorrhagic teleangiectasia","volume":"17","author":"Argyriou","year":"2006","journal-title":"Int. J. Mol. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1002\/humu.20342","article-title":"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","volume":"27","author":"Bossler","year":"2006","journal-title":"Hum. Mutat."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1002\/humu.20017","article-title":"Molecular screening of ALK1\/ACVRL1 and ENG genes in hereditary hemorrhagic telangiectasia in France","volume":"23","author":"Lesca","year":"2004","journal-title":"Hum. Mutat."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1111\/cge.12612","article-title":"Mutation analysis in Norwegian families with hereditary hemorrhagic telangiectasia: Founder mutations in ACVRL1","volume":"89","author":"Heimdal","year":"2016","journal-title":"Clin. Genet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1007\/s00439-010-0825-4","article-title":"Update on molecular diagnosis of hereditary hemorrhagic telangiectasia","volume":"128","author":"Grant","year":"2010","journal-title":"Hum. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"258","DOI":"10.2353\/jmoldx.2007.060117","article-title":"Clinical and analytical sensitivities in hereditary hemorrhagic telangiectasia testing and a report of de novo mutations","volume":"9","author":"Gedge","year":"2007","journal-title":"J. Mol. Diagn."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2829","DOI":"10.1002\/ajmg.a.35622","article-title":"Brain arteriovenous malformations associated with hereditary hemorrhagic telangiectasia: Gene-phenotype correlations","volume":"158a","author":"Nishida","year":"2012","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1007\/s10038-007-0187-5","article-title":"Analysis of ENG and ACVRL1 genes in 137 HHT Italian families identifies 76 different mutations (24 novel). Comparison with other European studies","volume":"52","author":"Olivieri","year":"2007","journal-title":"J. Hum. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Fontalba, A., Fernandez-L, A., Garc\u00eda-Alegria, E., Albi\u00f1ana, V., Garrido-Martin, E.M., Blanco, F.J., Zarrabeitia, R., Perez-Molino, A., Bernabeu-Herrero, M.E., and Ojeda, M.-L. (2008). Mutation study of Spanish patients with Hereditary Hemorrhagic Telangiectasia. BMC Med. Genet., 9.","DOI":"10.1186\/1471-2350-9-75"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1002\/lt.20544","article-title":"ALK-1 mutations in liver transplanted patients with hereditary hemorrhagic telangiectasia","volume":"11","author":"Argyriou","year":"2005","journal-title":"Liver Transpl."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1007\/s00439-004-1196-5","article-title":"Hereditary hemorrhagic telangiectasia: ENG and ALK-1 mutations in Dutch patients","volume":"116","author":"Letteboer","year":"2005","journal-title":"Hum. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1111\/j.1399-0004.2010.01596.x","article-title":"Molecular diagnosis in hereditary hemorrhagic telangiectasia: Findings in a series tested simultaneously by sequencing and deletion\/duplication analysis","volume":"79","author":"McDonald","year":"2011","journal-title":"Clin. Genet."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1111\/j.1399-0004.2008.01029.x","article-title":"Detection of a significant association between mutations in the ACVRL1 gene and hepatic involvement in German patients with hereditary haemorrhagic telangiectasia","volume":"74","author":"Brakensiek","year":"2008","journal-title":"Clin. Genet."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1002\/humu.22904","article-title":"Pulmonary Arterial Hypertension: A Current Perspective on Established and Emerging Molecular Genetic Defects","volume":"36","author":"Machado","year":"2015","journal-title":"Hum. Mutat."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1086\/513903","article-title":"The Activin Receptor-Like Kinase 1 Gene: Genomic Structure and Mutations in Hereditary Hemorrhagic Telangiectasia Type 2","volume":"61","author":"Berg","year":"1997","journal-title":"Am. J. Hum. Genet."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","article-title":"The mutational constraint spectrum quantified from variation in 141,456 humans","volume":"581","author":"Karczewski","year":"2020","journal-title":"Nature"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"D536","DOI":"10.1093\/nar\/gkaa1034","article-title":"jMorp updates in 2020: Large enhancement of multi-omics data resources on the general Japanese population","volume":"49","author":"Tadaka","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Choi, Y., Sims, G.E., Murphy, S., Miller, J.R., and Chan, A.P. (2012). Predicting the Functional Effect of Amino Acid Substitutions and Indels. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0046688"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2129","DOI":"10.1101\/gr.772403","article-title":"PANTHER: A library of protein families and subfamilies indexed by function","volume":"13","author":"Thomas","year":"2003","journal-title":"Genome Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.1093\/hmg\/ddu531","article-title":"Functional analysis of endoglin mutations from hereditary hemorrhagic telangiectasia type 1 patients reveals different mechanisms for endoglin loss of function","volume":"24","author":"Mallet","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1492","DOI":"10.1016\/j.bbadis.2013.05.016","article-title":"The ALK-1\/Smad1 pathway in cardiovascular physiopathology. A new target for therapy?","volume":"1832","year":"2013","journal-title":"Biochim. Biophys. Acta (BBA) Mol. Basis Dis."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"36990","DOI":"10.1074\/jbc.M112.365932","article-title":"Structure of the bone morphogenetic protein receptor ALK2 and implications for fibrodysplasia ossificans progressiva","volume":"287","author":"Chaikuad","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.cytogfr.2020.09.003","article-title":"Receptor binding competition: A paradigm for regulating TGF-\u03b2 family action","volume":"57","author":"Sundan","year":"2021","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1126\/science.287.5450.92","article-title":"Structural basis of Smad2 recognition by the Smad anchor for receptor activation","volume":"287","author":"Wu","year":"2000","journal-title":"Science"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.1016\/S1097-2765(01)00421-X","article-title":"Crystal Structure of a Phosphorylated Smad2: Recognition of Phosphoserine by the MH2 Domain and Insights on Smad Function in TGF-\u03b2 Signaling","volume":"8","author":"Wu","year":"2001","journal-title":"Mol. Cell"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"4950","DOI":"10.1038\/s41467-021-25248-5","article-title":"Structural basis for ALK2\/BMPR2 receptor complex signaling through kinase domain oligomerization","volume":"12","author":"Agnew","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2881","DOI":"10.1091\/mbc.12.9.2881","article-title":"Transforming Growth Factor \u03b2 Receptor Signaling and Endocytosis Are Linked through a COOH Terminal Activation Motif in the Type I Receptor","volume":"12","author":"Garamszegi","year":"2001","journal-title":"Mol. Biol. Cell"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1091\/mbc.12.3.675","article-title":"Mechanisms of transforming growth factor-beta receptor endocytosis and intracellular sorting differ between fibroblasts and epithelial cells","volume":"12","author":"Yao","year":"2001","journal-title":"Mol. Biol. Cell"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1002\/humu.21445","article-title":"Performance of mutation pathogenicity prediction methods on missense variants","volume":"32","author":"Thusberg","year":"2011","journal-title":"Hum. Mutat."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1581","DOI":"10.1038\/ng.3703","article-title":"M-CAP eliminates a majority of variants of uncertain significance in clinical exomes at high sensitivity","volume":"48","author":"Jagadeesh","year":"2016","journal-title":"Nat. Genet."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1016\/j.ajhg.2016.08.016","article-title":"REVEL: An Ensemble Method for Predicting the Pathogenicity of Rare Missense Variants","volume":"99","author":"Ioannidis","year":"2016","journal-title":"Am. J. Hum. Genet."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"19877","DOI":"10.1074\/jbc.RA119.010943","article-title":"BMP10 preserves cardiac function through its dual activation of SMAD-mediated and STAT3-mediated pathways","volume":"294","author":"Qu","year":"2019","journal-title":"J. Biol. Chem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"eaav5183","DOI":"10.1126\/scisignal.aav5183","article-title":"Specificity, versatility, and control of TGF-beta family signaling","volume":"12","author":"Derynck","year":"2019","journal-title":"Sci. Signal."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2028","DOI":"10.1038\/emboj.2009.162","article-title":"TAK1 is an essential regulator of BMP signalling in cartilage","volume":"28","author":"Shim","year":"2009","journal-title":"EMBO J."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1038\/ng.3837","article-title":"Pathogenic variants that alter protein code often disrupt splicing","volume":"49","author":"Soemedi","year":"2017","journal-title":"Nat. Genet."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1089\/1066527041410418","article-title":"Maximum entropy modeling of short sequence motifs with applications to RNA splicing signals","volume":"11","author":"Yeo","year":"2004","journal-title":"J. Comput. Biol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1038\/sj.ejhg.5200919","article-title":"Disease-associated mutations in conserved residues of ALK-1 kinase domain","volume":"11","author":"Abdalla","year":"2003","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1007\/s10456-014-9457-y","article-title":"A small molecule targeting ALK1 prevents Notch cooperativity and inhibits functional angiogenesis","volume":"18","author":"Kerr","year":"2015","journal-title":"Angiogenesis"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"3672","DOI":"10.1074\/jbc.274.6.3672","article-title":"Smad1 recognition and activation by the ALK1 group of transforming growth factor-beta family receptors","volume":"274","author":"Chen","year":"1999","journal-title":"J. Biol. Chem."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/12\/15\/5002\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:22:12Z","timestamp":1760127732000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/12\/15\/5002"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,29]]},"references-count":62,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2023,8]]}},"alternative-id":["jcm12155002"],"URL":"https:\/\/doi.org\/10.3390\/jcm12155002","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,29]]}}}