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

Toru Fukuda, Kazuhiro Kanomata, Junya Nojima, Shoichiro Kokabu, Masumi Akita, Kenji Ikebuchi, Eijiro Jimi, Tetsuo Komori, Yuichi Maruki, Masaru Matsuoka, Kohei Miyazono, Konosuke Nakayama, Akira Nanba, Hiroshi Tomoda, Yasushi Okazaki, Akira Ohtake, Hiromi Oda, Ichiro Owan, Tetsuya Yoda, Nobuhiko HagaHirokazu Furuya, Takenobu Katagiri

Research output: Contribution to journalArticlepeer-review

55 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)905-909
Number of pages5
JournalBiochemical and Biophysical Research Communications
Volume377
Issue number3
DOIs
Publication statusPublished - Dec 19 2008
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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