Abstract
Activin receptor-like kinase 2 (ALK2), also known as Activin A receptor type 1 (ACVR1), is a transmembrane kinase receptor for members of the transforming growth factor-β family. Wild-type ALK2/ACVR1 transduces osteogenic signaling in response to ligand binding. Fifteen years ago, a gain-of-function mutation in the ALK2/ACVR1 gene was detected in patients with the genetic disorder fibro-dysplasia ossificans progressiva, which is characterized by heterotopic ossification in soft tissues. Additional disorders, such as diffuse intrinsic pontin glioma, diffuse idiopathic skeletal hyperostosis, primary focal hyperhidrosis, and congenital heart defects, have also been found to be associated with ALK2/ACVR1. These findings further expand in vitro and in vivo model system research and promote our understanding of the molecular mechanisms of the pathogenesis and development of novel therapeutics and diagnosis for disorders associated with ALK2/ACVR1. Through aggressive efforts, some of the disorders associated with ALK2/ACVR1 will be overcome in the near future.
Highlights
In 2006, a rare genetic disorder involving the skeletal muscle, called fibro-dysplasia ossificans progressiva (FOP; OMIM #135100), was reported to be associated with a recurrent mutation in the Activin A receptor type I (ACVR1) gene, which encodes the transmembrane receptor Activin receptor-like kinase 2 (ALK2)/ACVR1 protein [1] (Figure 1)
Patients with FOP carrying the p.delP197_F198insL mutation exhibited equivalent or milder clinical features than those with typical FOP [38]. These findings suggest that a mechanism other than FKBP12 is involved in the activation of mutant ALK2/ACVR1 in patients with FOP
ALK2/ACVR1 is a type I receptor for transforming growth factor-β (TGF-β) family members, especially osteogenic ligands that activate intracellular signaling through Smad1 and Smad5
Summary
In 2006, a rare genetic disorder involving the skeletal muscle, called fibro-dysplasia ossificans progressiva (FOP; OMIM #135100), was reported to be associated with a recurrent mutation in the Activin A receptor type I (ACVR1) gene, which encodes the transmembrane receptor Activin receptor-like kinase 2 (ALK2)/ACVR1 protein [1] (Figure 1). The ALK2/ACVR1 protein serves as a receptor for members of the transforming growth factor-β (TGF-β) family, especially for members inducing osteogenic signaling, such as bone morphogenetic proteins (BMPs). Experimental gene targeting and natural genetic disorders in molecules associated with BMP signaling, such as ligands and receptors, suggest that BMPs regulate the development of various organs in addition to the skeletal tissues, including teeth, skeletal muscle, tendons, ligaments, brain, eye, heart, lung, kidney, colon, and reproductive tissues. An aspect of this knowledge was found in relation to human disorders in ALK2/ACVR1.
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