A unique mutation of ALK2, G356D, found in a patient with fibrodysplasia ossificans progressiva is a moderately activated BMP type I receptor

• Published in: Biochemical and biophysical research communications 2008-12, Vol.377 (3), p.905-909
• Main Authors: Fukuda, Toru, Kanomata, Kazuhiro, Nojima, Junya, Kokabu, Shoichiro, Akita, Masumi, Ikebuchi, Kenji, Jimi, Eijiro, Komori, Tetsuo, Maruki, Yuichi, Matsuoka, Masaru, Miyazono, Kohei, Nakayama, Konosuke, Nanba, Akira, Tomoda, Hiroshi, Okazaki, Yasushi, Ohtake, Akira, Oda, Hiromi, Owan, Ichiro, Yoda, Tetsuya, Haga, Nobuhiko, Furuya, Hirokazu, Katagiri, Takenobu
• Format: Article
• Language: English
• Subjects: Activin Receptors, Type I - antagonists & inhibitors; Activin Receptors, Type I - genetics; Activin Receptors, Type I - metabolism; Amino Acid Substitution; Animals; Aspartic Acid - genetics; Aspartic Acid - metabolism; BMP; Bone Morphogenetic Protein Receptors, Type I - agonists; Bone Morphogenetic Protein Receptors, Type I - antagonists & inhibitors; Bone Morphogenetic Protein Receptors, Type I - metabolism; Cell Differentiation; Glycine - genetics; Glycine - metabolism; Heterotopic bone formation; Humans; Ligands; Mice; Muscle; Muscle Development - drug effects; Muscle Development - genetics; Mutation; Myoblasts - drug effects; Myoblasts - metabolism; Myositis Ossificans - enzymology; Myositis Ossificans - genetics; Osteoblasts - drug effects; Pyrazoles - pharmacology; Pyrimidines - pharmacology; Receptor; Signal Transduction; Signaling; Smad Proteins - metabolism
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2008.10.093

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant congenital disorder characterized by progressive heterotopic bone formation in muscle tissues. A common mutation among FOP patients has been identified in ALK2, ALK2(R206H), which encodes a constitutively active bone morphogenetic protein (BMP) receptor. Recently, a unique mutation of ALK2, ALK2(G356D), was identified to be a novel mutation in a Japanese FOP patient who had unique clinical features. Over-expression of ALK2(G356D) induced phosphorylation of Smad1/5/8 and activated Id1-luc and alkaline phosphatase activity in myoblasts. However, the over-expression failed to activate phosphorylation of p38, ERK1/2, and CAGA-luc activity. These ALK2(G356D) activities were weaker than those of ALK2(R206H), and they were suppressed by a specific inhibitor of the BMP-regulated Smad pathway. These findings suggest that ALK2(G356D) induces heterotopic bone formation via activation of a BMP-regulated Smad pathway. The quantitative difference between ALK2(G356D) and ALK2(R206H) activities may have caused the phenotypic differences in these patients.