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

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.

Fig. 1

Anatomical and histological characteristics of FOP and DIPG. (A–B) Images of an FOP patient showing the progression and increased severity of HO legions along the back at indicated times. Images are from friendswithfop.com. (C) Histological organization of an HO lesion showing the presence of cartilage (arrow) and bone (double arrow) and reflecting the endochondral nature of HO in FOP. Section was stained with hematoxylin & eosin. (D) CT scans from a DIPG patient showing presence of the tumor mass in the pons (arrows). Images are from northwestern.edu/saratsis/.

Fig. 2

Schematic showing the number and location of missense mutations in ACVR1 reported so far in DIPG and FOP. Note that all mutations found in DIPG tumors have been found in FOP patients with the exception of G328V (in red).

Fig. 3

Schematics depicting possible roles of mutant ACVR1/ALK2 in the pathogenesis of FOP and DIPG. In FOP, mutations in ACVR1 are known to be necessary and sufficient to cause HO and skeletal problems typical of FOP. The mutations are likely to occur during gametogenesis or very early embryogenesis, and eventually work in concert with local ligands and inflammation (indicated by *) to initiate and sustain a cascade of events that start with recruitment of progenitor cells and culminate with formation of endochondral bone at extraskeletal sites over postnatal life. The various gene regulators controlling each step of the HO process are those previously shown to normally regulate endochondral bone formation in embryos and growing organisms and are assumed to be operating in HO as well. In DIPG, mutations in ACVR1 are currently thought to be not sufficient to cause tumor formation, and possible ligands for the mutant receptors remain unknown as well (indicated by **). The four pathogenic pathways shown here to which mutant ACVR1 could contribute are based on: previous extensive studies on genomic landscapes and transcriptome analyses in cohorts of DIPG patients; and roles that wild type ACVR1 is known to have in other developmental processes and systems. These pathogenic pathways are meant to suggest possible gene interactions that mutant ACVR1 could have with other known DIPG gene mutations/alterations and what specific cell functions and behaviors could in turn be affected.