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) receptors. 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.

Novel asymptomatic CNS findings in patients withACVR1/ALK2mutations causing fibrodysplasia ossificans progressiva

“…With the exception of G328V, all these mutations are identical to those identified in patients with FOP. Of note, the vast majority (95%) of patients with FOP harbours the classic R206H mutation, while a wider spectrum of ACVR1/ALK2 mutations is encountered in DIPG 20. On MRI, DIPG are completely different, diffusely infiltrative, intrinsic lesions, expanding the pons with possible associated haemorrhagic or necrotic-cystic changes 19.…”

Bone Morphogenetic Proteins

“…Like BMP agonists, small molecule inhibitors specific for BMP signaling have been developed (Yu et al 2008a;Hong and Yu 2009;Boergermann et al 2010;Mohedas et al 2013;Sanvitale et al 2013;Tsugawa et al 2014). These inhibitors appear to be useful for the treatment of various diseases that are caused by activation of BMP signals, such as FOP (Yu et al 2008b), DIPG (Pacifici and Shore 2016), and metastasis in certain types of cancer.…”

“…Moreover, a neutralizing antibody against activin A inhibits heterotopic bone formation in model mice of FOP (Hastell et al 2015). It is of note that common activating mutations in ALK-2 found in FOP patients are related to the pathogenesis of diffuse intrinsic pontine gliomas (DIPGs), a rare type of glioma that occurs exclusively in children (Pacifici and Shore 2016).…”

Fibrodysplasia ossificans progressiva: Basic understanding and experimental models

“…The nature of FOP is particularly problematic because of the difficulty in acquiring living tissue to study the mechanisms of the disease. Minor trauma or an infection may cause tissue swelling followed by development of HO in the ligaments and connective tissue (15). At present, the main models used to study the pathogenesis of FOP are mouse cells, knockout mice, and induced pluripotent stem cells (25).…”

“…Eighty percent of patients with this mutation may have a congenital big toe (hallux valgus deformity), and some may exhibit soft tissue swelling leading to the formation of abnormal bone in the first decade of life (15). More than 90% of "classic" patients have a tumor in the tibia and more than 80% have a vertebral deformity (16).…”