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Gene Review

ACVRL1  -  activin A receptor type II-like 1

Homo sapiens

Synonyms: ACVRLK1, ALK-1, ALK1, Activin receptor-like kinase 1, HHT, ...
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Disease relevance of ACVRL1

  • In some families in whom a form of idiopathic pulmonary arterial hypertension cosegregated with HHT, mutations in the ACVRL1 gene were present [1].
  • Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disease characterized by arteriovenous malformations and resulting from mutations in two major genes: ENG and ACVRL1 [2].
  • Identification of 13 new mutations in the ACVRL1 gene in a group of 52 unselected Italian patients affected by hereditary haemorrhagic telangiectasia [3].
  • METHODS: The coding sequence (in 44 patients with AVMs and 27 with aneurysms) and the 5' end and the polyA site (in 53 patients with AVMs) of the ACVRL1 gene were analyzed for sequence variations using direct sequencing and single-strand conformational polymorphism analysis [4].
  • One ENG and three ACVRL1 gene polymorphisms were genotyped using restriction enzyme-based analysis in 101 patients with sporadic AVMs and DAVFs of the CNS, 79 patients treated for intracranial aneurysms, and 202 control volunteers [4].

Psychiatry related information on ACVRL1

  • In endothelial cells, TGF-beta binds to two distinct type I receptor serine-threonine kinases, ALK-5 and ALK-1; the latter activates the same R-Smads that are activated by BMP and induces synthesis of Id (inhibitor of differentiation or inhibitor of DNA binding) proteins [5].

High impact information on ACVRL1


Chemical compound and disease context of ACVRL1


Biological context of ACVRL1


Anatomical context of ACVRL1


Associations of ACVRL1 with chemical compounds


Physical interactions of ACVRL1

  • Their structural properties suggest that ALK-1 to -4 are receptors that may bind ligands that are members of the TGF-beta superfamily [19].
  • Using the two-hybrid system, we identified an ALK1-binding protein encoded by an ancient retroviral/retrotransposon element integrated as a single copy gene known as PEG10 on human chromosome 7q21 [23].
  • Interestingly, SKR-3 could interact with both CUL-1 and its close paralog CUL-6 [24].

Other interactions of ACVRL1

  • We report three mutations in the coding sequence of the ALK1 gene in those families which show linkage of the ORW phenotype to chromosome 12 [15].
  • In HUVEC, ALK-1 was not detectable in the TGF-beta1 or -beta3 receptor complexes [16].
  • TEK and ACVRL1 could essentially be excluded [25].
  • DNA from the proband of each family was sequenced for the ACVRL1, ENG, and MADH4 genes [26].
  • In COS-1 transfected cells, ALK-1 was found in the TGF-beta1 and -beta3 receptor complexes in association with endoglin and TbetaRII, but not in activin receptor complexes containing endoglin [16].

Analytical, diagnostic and therapeutic context of ACVRL1

  • However, in the absence of ligand, ALK-1 and endoglin interactions were observed by immunoprecipitation/western blot in HUVEC from normal as well as HHT1 and HHT2 patients [16].
  • We report here on the genetic and molecular heterogeneity found in the HHT population in the Netherlands. Probands of 104 apparently unrelated families were studied and we performed sequence analysis on both the ENG gene and ALK-1 gene [27].
  • To identify downstream genes implicated in ALK-1 cellular responses, we next performed a cDNA array analysis of the expressed genes [28].
  • We performed temperature gradient capillary electrophoresis and full gene sequencing of both ACVRL1 and ENG genes [29].
  • The high rate of detection of mutations by genomic sequencing of ALK-1 suggests that this will be a useful diagnostic test for HHT2, particularly where preliminary linkage to chromosome 12q13 can be established [30].


  1. Echocardiographic screening discloses increased values of pulmonary artery systolic pressure in 9 of 68 unselected patients affected with hereditary hemorrhagic telangiectasia. Olivieri, C., Lanzarini, L., Pagella, F., Semino, L., Corno, S., Valacca, C., Plauchu, H., Lesca, G., Barthelet, M., Buscarini, E., Danesino, C. Genet. Med. (2006) [Pubmed]
  2. Distribution of ENG and ACVRL1 (ALK1) mutations in French HHT patients. Lesca, G., Burnichon, N., Raux, G., Tosi, M., Pinson, S., Marion, M.J., Babin, E., Gilbert-Dussardier, B., Rivière, S., Goizet, C., Faivre, L., Plauchu, H., Frébourg, T., Calender, A., Giraud, S. Hum. Mutat. (2006) [Pubmed]
  3. Identification of 13 new mutations in the ACVRL1 gene in a group of 52 unselected Italian patients affected by hereditary haemorrhagic telangiectasia. Olivieri, C., Mira, E., Delù, G., Pagella, F., Zambelli, A., Malvezzi, L., Buscarini, E., Danesino, C. J. Med. Genet. (2002) [Pubmed]
  4. Association of a polymorphism of the ACVRL1 gene with sporadic arteriovenous malformations of the central nervous system. Simon, M., Franke, D., Ludwig, M., Aliashkevich, A.F., Köster, G., Oldenburg, J., Boström, A., Ziegler, A., Schramm, J. J. Neurosurg. (2006) [Pubmed]
  5. Id: a target of BMP signaling. Miyazono, K., Miyazawa, K. Sci. STKE (2002) [Pubmed]
  6. Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. Trembath, R.C., Thomson, J.R., Machado, R.D., Morgan, N.V., Atkinson, C., Winship, I., Simonneau, G., Galie, N., Loyd, J.E., Humbert, M., Nichols, W.C., Morrell, N.W., Berg, J., Manes, A., McGaughran, J., Pauciulo, M., Wheeler, L. N. Engl. J. Med. (2001) [Pubmed]
  7. Therapeutic action of tranexamic acid in hereditary haemorrhagic telangiectasia (HHT): Regulation of ALK-1/endoglin pathway in endothelial cells. Fernandez-L, A., Garrido-Martin, E.M., Sanz-Rodriguez, F., Ramirez, J.R., Morales-Angulo, C., Zarrabeitia, R., Perez-Molino, A., Bernabéu, C., Botella, L.M. Thromb. Haemost. (2007) [Pubmed]
  8. ALK gene products in anaplastic large cell lymphomas and Hodgkin's disease. Herbst, H., Anagnostopoulos, J., Heinze, B., Dürkop, H., Hummel, M., Stein, H. Blood (1995) [Pubmed]
  9. Growth of several cariogenic strains of oral streptococci in a chemically defined medium. Terleckyj, B., Willett, N.P., Shockman, G.D. Infect. Immun. (1975) [Pubmed]
  10. Inflammatory myofibroblastic tumor in children: clinical review with anaplastic lymphoma kinase, Epstein-Barr virus, and human herpesvirus 8 detection analysis. Mergan, F., Jaubert, F., Sauvat, F., Hartmann, O., Lortat-Jacob, S., Révillon, Y., Nihoul-Fékété, C., Sarnacki, S. J. Pediatr. Surg. (2005) [Pubmed]
  11. Eicosanoid production by density-defined human peritoneal macrophages during inflammation. Pruimboom, W.M., Vollebregt, M.J., Zijlstra, F.J., Bonta, I.L., Wilson, J.H. Agents Actions (1992) [Pubmed]
  12. 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. Bossler, A.D., Richards, J., George, C., Godmilow, L., Ganguly, A. Hum. Mutat. (2006) [Pubmed]
  13. Genotype-phenotype correlation in hereditary hemorrhagic telangiectasia: mutations and manifestations. Bayrak-Toydemir, P., McDonald, J., Markewitz, B., Lewin, S., Miller, F., Chou, L.S., Gedge, F., Tang, W., Coon, H., Mao, R. Am. J. Med. Genet. A (2006) [Pubmed]
  14. High frequency of ENG and ALK1/ACVRL1 mutations in German HHT patients. Schulte, C., Geisthoff, U., Lux, A., Kupka, S., Zenner, H.P., Blin, N., Pfister, M. Hum. Mutat. (2005) [Pubmed]
  15. Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. Johnson, D.W., Berg, J.N., Baldwin, M.A., Gallione, C.J., Marondel, I., Yoon, S.J., Stenzel, T.T., Speer, M., Pericak-Vance, M.A., Diamond, A., Guttmacher, A.E., Jackson, C.E., Attisano, L., Kucherlapati, R., Porteous, M.E., Marchuk, D.A. Nat. Genet. (1996) [Pubmed]
  16. Analysis of ALK-1 and endoglin in newborns from families with hereditary hemorrhagic telangiectasia type 2. Abdalla, S.A., Pece-Barbara, N., Vera, S., Tapia, E., Paez, E., Bernabeu, C., Letarte, M. Hum. Mol. Genet. (2000) [Pubmed]
  17. Mutation analysis in Spanish patients with hereditary hemorrhagic telangiectasia: deficient endoglin up-regulation in activated monocytes. Sanz-Rodriguez, F., Fernandez-L, A., Zarrabeitia, R., Perez-Molino, A., Ramírez, J.R., Coto, E., Bernabeu, C., Botella, L.M. Clin. Chem. (2004) [Pubmed]
  18. Genomic analyses facilitate identification of receptors and signalling pathways for growth differentiation factor 9 and related orphan bone morphogenetic protein/growth differentiation factor ligands. Mazerbourg, S., Hsueh, A.J. Hum. Reprod. Update (2006) [Pubmed]
  19. Activin receptor-like kinases: a novel subclass of cell-surface receptors with predicted serine/threonine kinase activity. ten Dijke, P., Ichijo, H., Franzén, P., Schulz, P., Saras, J., Toyoshima, H., Heldin, C.H., Miyazono, K. Oncogene (1993) [Pubmed]
  20. The conventional transforming growth factor-beta (TGF-beta) receptor type I is not required for TGF-beta 1 signaling in a human prostate cancer cell line, LNCaP. Kim, I.Y., Zelner, D.J., Lee, C. Exp. Cell Res. (1998) [Pubmed]
  21. Involvement of bone morphogenetic protein-6 in differential regulation of aldosterone production by angiotensin II and potassium in human adrenocortical cells. Inagaki, K., Otsuka, F., Suzuki, J., Kano, Y., Takeda, M., Miyoshi, T., Otani, H., Mimura, Y., Ogura, T., Makino, H. Endocrinology (2006) [Pubmed]
  22. AT1 antagonist modulates activin-like kinase 5 and TGF-beta receptor II in the developing kidney. Yim, H.E., Kim, M.K., Bae, I.S., Kim, J.H., Choi, B.M., Yoo, K.H., Hong, Y.S., Lee, J.W. Pediatr. Nephrol. (2006) [Pubmed]
  23. Human retroviral gag- and gag-pol-like proteins interact with the transforming growth factor-beta receptor activin receptor-like kinase 1. Lux, A., Beil, C., Majety, M., Barron, S., Gallione, C.J., Kuhn, H.M., Berg, J.N., Kioschis, P., Marchuk, D.A., Hafner, M. J. Biol. Chem. (2005) [Pubmed]
  24. The Caenorhabditis elegans Skp1-related gene family: diverse functions in cell proliferation, morphogenesis, and meiosis. Nayak, S., Santiago, F.E., Jin, H., Lin, D., Schedl, T., Kipreos, E.T. Curr. Biol. (2002) [Pubmed]
  25. Familial predisposition to tufted angioma: identification of blood and lymphatic vascular components. Tille, J.C., Morris, M.A., Bründler, M.A., Pepper, M.S. Clin. Genet. (2003) [Pubmed]
  26. A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4). Gallione, C.J., Repetto, G.M., Legius, E., Rustgi, A.K., Schelley, S.L., Tejpar, S., Mitchell, G., Drouin, E., Westermann, C.J., Marchuk, D.A. Lancet (2004) [Pubmed]
  27. Hereditary hemorrhagic telangiectasia: ENG and ALK-1 mutations in Dutch patients. Letteboer, T.G., Zewald, R.A., Kamping, E.J., de Haas, G., Mager, J.J., Snijder, R.J., Lindhout, D., Hennekam, F.A., Westermann, C.J., Ploos van Amstel, J.K. Hum. Genet. (2005) [Pubmed]
  28. Activin receptor-like kinase 1 is implicated in the maturation phase of angiogenesis. Lamouille, S., Mallet, C., Feige, J.J., Bailly, S. Blood (2002) [Pubmed]
  29. Clinical and analytical sensitivities in hereditary hemorrhagic telangiectasia testing and a report of de novo mutations. Gedge, F., McDonald, J., Phansalkar, A., Chou, L.S., Calderon, F., Mao, R., Lyon, E., Bayrak-Toydemir, P. The Journal of molecular diagnostics : JMD (2007) [Pubmed]
  30. The activin receptor-like kinase 1 gene: genomic structure and mutations in hereditary hemorrhagic telangiectasia type 2. Berg, J.N., Gallione, C.J., Stenzel, T.T., Johnson, D.W., Allen, W.P., Schwartz, C.E., Jackson, C.E., Porteous, M.E., Marchuk, D.A. Am. J. Hum. Genet. (1997) [Pubmed]
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