Common mutations in ALK2/ACVR1, a multi-faceted receptor, have roles in distinct pediatric musculoskeletal and neural orphan disorders. (February 2016)

• Record Type: Journal Article
• Authors: Pacifici, Maurizio; Shore, Eileen M.
• Is Part Of: Cytokine & growth factor reviews. Volume 27(2016)
• Page Start: 93
• Page End: 104
• Publication Date: 2016-02
• Subjects: ACVR1 -- ALK2 -- Fibrodysplasia Ossificans Progressiva -- Diffuse Intrinsic Pontine Gliomas -- Orphan diseases -- BMP signaling; Cytokines -- Periodicals; 571.84
• DOI: 10.1016/j.cytogfr.2015.12.007
• Languages: English
• ISSNs: 1359-6101

Abstract

Graphical abstract: Highlights: ALK2, the product of ACVR1, is a member of the type I bone morphogenetic protein (BMP) receptors. ALK2 and the BMP signaling pathway have essential roles in skeletal and neural development and homeostasis. Common activating ACVR1 mutations have been identified in the pediatric disorders FOP and DIPG. Analysis and comparison of respective pathogenic mechanisms will help to identify therapeutics for these severe and often fatal conditions. 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.