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

T Fukuda, K Kanomata, J Nojima, S Kokabu… - Biochemical and …, 2008 - Elsevier
T Fukuda, K Kanomata, J Nojima, S Kokabu, M Akita, K Ikebuchi, E Jimi, T Komori, Y Maruki…
Biochemical and biophysical research communications, 2008Elsevier
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) …
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.
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