Common mutations in ALK2/ACVR1, a multi-faceted receptor, have roles in distinct pediatric musculoskeletal and neural orphan disorders

Cytokine Growth Factor Rev. 2016 Feb:27:93-104. doi: 10.1016/j.cytogfr.2015.12.007. Epub 2015 Dec 28.

Abstract

Activin receptor-like kinase-2 (ALK2), the product of ACVR1, is a member of the type I bone morphogenetic protein (BMP) receptor family. ALK2 exerts key and non-redundant roles in numerous developmental processes, including the specification, growth and morphogenesis of endochondral skeletal elements. There is also strong evidence that BMP signaling plays important roles in determination, differentiation and function of neural cells and tissues. Here we focus on the intriguing discovery that common activating mutations in ALK2 occur in Fibrodysplasia Ossificans Progressiva (FOP) and Diffuse Intrinsic Pontine Gliomas (DIPGs), distinct pediatric disorders of significant severity that are associated with premature death. Pathogenesis and treatment remain elusive for both. We consider recent studies on the nature of the ACVR1 mutations, possible modes of action and targets, and plausible therapeutic measures. Comparisons of the diverse - but genetically interrelated - pathologies of FOP and DIPG will continue to be of major mutual benefit with broad biomedical and clinical relevance.

Keywords: ACVR1; ALK2; BMP signaling; Diffuse Intrinsic Pontine Gliomas; Fibrodysplasia Ossificans Progressiva; Orphan diseases.

Publication types

  • Review

MeSH terms

  • Activin Receptors, Type I* / genetics
  • Activin Receptors, Type I* / metabolism
  • Animals
  • Brain Stem Neoplasms* / genetics
  • Brain Stem Neoplasms* / metabolism
  • Glioma* / genetics
  • Humans
  • Mutation*
  • Myositis Ossificans* / genetics
  • Myositis Ossificans* / metabolism
  • Neoplasm Proteins* / genetics
  • Neoplasm Proteins* / metabolism

Substances

  • Neoplasm Proteins
  • ACVR1 protein, human
  • Activin Receptors, Type I