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ACVR1 gene

activin A receptor type 1
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Normal Function

The ACVR1 gene provides instructions for making the activin receptor type-1 (ACVR1) protein, which is a member of a protein family called bone morphogenetic protein (BMP) type I receptors. BMP receptors span the cell membrane, so that one end of the protein remains inside the cell and the other end projects from the outer surface of the cell. This arrangement allows receptors to receive signals from outside the cell and transmit them inside to affect cell development and function.

The ACVR1 protein is found in many tissues of the body including skeletal muscle and cartilage. It helps to control the growth and development of the bones and muscles, including the gradual replacement of cartilage by bone (ossification). This process occurs in normal skeletal maturation from birth to young adulthood.

The ACVR1 protein is normally turned on (activated) at appropriate times by molecules called ligands. Activation may occur when these ligands, such as BMPs or a protein called activin A, attach (bind) to the receptor or to other proteins with which it forms a complex. Another protein called FKBP12 can turn off (inhibit) ACVR1 by binding to the receptor and preventing inappropriate (leaky) activation in the absence of ligands.

Health Conditions Related to Genetic Changes

Fibrodysplasia ossificans progressiva

Mutations in the ACVR1 gene cause fibrodysplasia ossificans progressiva, a disorder in which muscles and connective tissue such as tendons and ligaments are gradually replaced by bone (ossified). The formation of bone tissue outside the skeleton freezes joints and limits movement in affected individuals. The most common mutation, which occurs in all individuals with the classic features of the condition, substitues the protein building block (amino acid) histidine for the amino acid arginine at position 206 of the ACVR1 protein (written as Arg206His or R206H). Other mutations in the ACVR1 gene cause rarer forms of the condition that can be more severe and often involve skeletal abnormalities, such as multiple abnormally formed fingers and toes.

Studies show that the R206H mutation changes the shape of the ACVR1 protein. This shape change disrupts the binding of the inhibitor protein FKBP12. As a result, the receptor is constantly turned on (constitutively activated), even in the absence of ligands. Other ACVR1 gene mutations result in a receptor protein that is turned on by ligands more easily than the normal version of the protein. Too much receptor activity causes overgrowth of bone and cartilage, resulting in the signs and symptoms of fibrodysplasia ossificans progressiva.

More About This Health Condition

Other Names for This Gene

  • activin A receptor type I
  • activin A receptor, type I
  • activin A receptor, type II-like kinase 2
  • activin A type I receptor
  • activin A type I receptor precursor
  • ActR-IA protein, human
  • ACTRI
  • ACVR1_HUMAN
  • ACVR1A
  • ACVRLK2
  • ALK2
  • hydroxyalkyl-protein kinase
  • SKR1

Additional Information & Resources

Tests Listed in the Genetic Testing Registry

Scientific Articles on PubMed

Catalog of Genes and Diseases from OMIM

Research Resources

References

  • Chen D, Zhao M, Mundy GR. Bone morphogenetic proteins. Growth Factors. 2004 Dec;22(4):233-41. Review. Citation on PubMed
  • de Sousa Lopes SM, Roelen BA, Monteiro RM, Emmens R, Lin HY, Li E, Lawson KA, Mummery CL. BMP signaling mediated by ALK2 in the visceral endoderm is necessary for the generation of primordial germ cells in the mouse embryo. Genes Dev. 2004 Aug 1;18(15):1838-49. Citation on PubMed or Free article on PubMed Central
  • Fiori JL, Billings PC, de la Peña LS, Kaplan FS, Shore EM. Dysregulation of the BMP-p38 MAPK signaling pathway in cells from patients with fibrodysplasia ossificans progressiva (FOP). J Bone Miner Res. 2006 Jun;21(6):902-9. Citation on PubMed
  • Groppe JC, Shore EM, Kaplan FS. Functional modeling of the ACVR1 (R206H) mutation in FOP. Clin Orthop Relat Res. 2007 Sep;462:87-92. Citation on PubMed
  • Kaplan FS, Glaser DL, Pignolo RJ, Shore EM. A new era for fibrodysplasia ossificans progressiva: a druggable target for the second skeleton. Expert Opin Biol Ther. 2007 May;7(5):705-12. Review. Citation on PubMed
  • Lin GT, Chang HW, Liu CS, Huang PJ, Wang HC, Cheng YM. De novo 617G-A nucleotide mutation in the ACVR1 gene in a Taiwanese patient with fibrodysplasia ossificans progressiva. J Hum Genet. 2006;51(12):1083-1086. doi: 10.1007/s10038-006-0069-2. Epub 2006 Nov 1. Citation on PubMed
  • Nakajima M, Haga N, Takikawa K, Manabe N, Nishimura G, Ikegawa S. The ACVR1 617G>A mutation is also recurrent in three Japanese patients with fibrodysplasia ossificans progressiva. J Hum Genet. 2007;52(5):473-475. doi: 10.1007/s10038-007-0128-3. Epub 2007 Mar 10. Citation on PubMed
  • O'Connell MP, Billings PC, Fiori JL, Deirmengian G, Roach HI, Shore EM, Kaplan FS. HSPG modulation of BMP signaling in fibrodysplasia ossificans progressiva cells. J Cell Biochem. 2007 Dec 15;102(6):1493-503. Citation on PubMed
  • Samad TA, Rebbapragada A, Bell E, Zhang Y, Sidis Y, Jeong SJ, Campagna JA, Perusini S, Fabrizio DA, Schneyer AL, Lin HY, Brivanlou AH, Attisano L, Woolf CJ. DRAGON, a bone morphogenetic protein co-receptor. J Biol Chem. 2005 Apr 8;280(14):14122-9. Epub 2005 Jan 25. Citation on PubMed
  • Shore EM, Xu M, Feldman GJ, Fenstermacher DA, Cho TJ, Choi IH, Connor JM, Delai P, Glaser DL, LeMerrer M, Morhart R, Rogers JG, Smith R, Triffitt JT, Urtizberea JA, Zasloff M, Brown MA, Kaplan FS. A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat Genet. 2006 May;38(5):525-7. Epub 2006 Apr 23. Erratum in: Nat Genet. 2007 Feb;39(2):276. FOP International Research Consortium [removed]; Cho, Tae-Joon [added]; Choi, In Ho [added]; Connor, J Michael [added]; Delai, Patricia [added]; Glaser, David L [added]; LeMerrer, Martine [added]; Morhart, Rolf [added]; Rogers, John G [added]; Smith, Roger. Citation on PubMed
  • Zhang D, Schwarz EM, Rosier RN, Zuscik MJ, Puzas JE, O'Keefe RJ. ALK2 functions as a BMP type I receptor and induces Indian hedgehog in chondrocytes during skeletal development. J Bone Miner Res. 2003 Sep;18(9):1593-604. Citation on PubMed
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