A novel mutation of ALK2, L196P, found in the most benign case of fibrodysplasia ossificans progressiva activates BMP-specific intracellular signaling equivalent to a typical mutation, R206H

Satoshi Ohte, Masashi Shin, Hiroki Sasanuma, Katsumi Yoneyama, Masumi Akita, Kenji Ikebuchi, Eijiro Jimi, Yuichi Maruki, Masaru Matsuoka, Akira Namba, Hiroshi Tomoda, Yasushi Okazaki, Akira Ohtake, Hiromi Oda, Ichiro Owan, Tetsuya Yoda, Hirokazu Furuya, Jyunji Kamizono, Hiroshi Kitoh, Yasuharu NakashimaTakafumi Susami, Nobuhiko Haga, Tetsuo Komori, Takenobu Katagiri

研究成果: ジャーナルへの寄稿記事

30 引用 (Scopus)

抄録

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant congenital disorder characterized by progressive heterotopic ossification in muscle tissues. Constitutively activated mutants of a bone morphogenetic protein (BMP) receptor, ALK2, have been identified in patients with FOP. Recently, a novel ALK2 mutation, L196P, was found in the most benign case of FOP reported thus far. In the present study, we examined the biological activities of ALK2(L196P) in vitro. Over-expression of ALK2(L196P) induced BMP-specific activities, including the suppression of myogenesis, the induction of alkaline phosphatase activity, increased BMP-specific luciferase reporter activity, and increased phosphorylation of Smad1/5 but not Erk1/2 or p38. The activities of ALK2(L196P) were higher than those of ALK2(G356D), another mutant ALK2 allele found in patients with FOP and were equivalent to those of ALK2(R206H), a typical mutation found in patients with FOP. ALK2(L196P) was equally or more resistant to inhibitors in comparison to ALK2(R206H). These findings suggest that ALK2(L196P) is an activated BMP receptor equivalent to ALK2(R206H) and that ALK2(L196P) activity may be suppressed in vivo by a novel molecular mechanism in patients with this mutation.

元の言語英語
ページ(範囲)213-218
ページ数6
ジャーナルBiochemical and Biophysical Research Communications
407
発行部数1
DOI
出版物ステータス出版済み - 4 1 2011

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Bone Morphogenetic Protein Receptors
Myositis Ossificans
Bone Morphogenetic Proteins
Mutation
Phosphorylation
Bioactivity
Luciferases
Alkaline Phosphatase
Muscle
Tissue
Heterotopic Ossification
Congenital, Hereditary, and Neonatal Diseases and Abnormalities
Muscle Development
Alleles
Muscles

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

これを引用

A novel mutation of ALK2, L196P, found in the most benign case of fibrodysplasia ossificans progressiva activates BMP-specific intracellular signaling equivalent to a typical mutation, R206H. / Ohte, Satoshi; Shin, Masashi; Sasanuma, Hiroki; Yoneyama, Katsumi; Akita, Masumi; Ikebuchi, Kenji; Jimi, Eijiro; Maruki, Yuichi; Matsuoka, Masaru; Namba, Akira; Tomoda, Hiroshi; Okazaki, Yasushi; Ohtake, Akira; Oda, Hiromi; Owan, Ichiro; Yoda, Tetsuya; Furuya, Hirokazu; Kamizono, Jyunji; Kitoh, Hiroshi; Nakashima, Yasuharu; Susami, Takafumi; Haga, Nobuhiko; Komori, Tetsuo; Katagiri, Takenobu.

:: Biochemical and Biophysical Research Communications, 巻 407, 番号 1, 01.04.2011, p. 213-218.

研究成果: ジャーナルへの寄稿記事

Ohte, S, Shin, M, Sasanuma, H, Yoneyama, K, Akita, M, Ikebuchi, K, Jimi, E, Maruki, Y, Matsuoka, M, Namba, A, Tomoda, H, Okazaki, Y, Ohtake, A, Oda, H, Owan, I, Yoda, T, Furuya, H, Kamizono, J, Kitoh, H, Nakashima, Y, Susami, T, Haga, N, Komori, T & Katagiri, T 2011, 'A novel mutation of ALK2, L196P, found in the most benign case of fibrodysplasia ossificans progressiva activates BMP-specific intracellular signaling equivalent to a typical mutation, R206H', Biochemical and Biophysical Research Communications, 巻. 407, 番号 1, pp. 213-218. https://doi.org/10.1016/j.bbrc.2011.03.001
Ohte, Satoshi ; Shin, Masashi ; Sasanuma, Hiroki ; Yoneyama, Katsumi ; Akita, Masumi ; Ikebuchi, Kenji ; Jimi, Eijiro ; Maruki, Yuichi ; Matsuoka, Masaru ; Namba, Akira ; Tomoda, Hiroshi ; Okazaki, Yasushi ; Ohtake, Akira ; Oda, Hiromi ; Owan, Ichiro ; Yoda, Tetsuya ; Furuya, Hirokazu ; Kamizono, Jyunji ; Kitoh, Hiroshi ; Nakashima, Yasuharu ; Susami, Takafumi ; Haga, Nobuhiko ; Komori, Tetsuo ; Katagiri, Takenobu. / A novel mutation of ALK2, L196P, found in the most benign case of fibrodysplasia ossificans progressiva activates BMP-specific intracellular signaling equivalent to a typical mutation, R206H. :: Biochemical and Biophysical Research Communications. 2011 ; 巻 407, 番号 1. pp. 213-218.
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abstract = "Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant congenital disorder characterized by progressive heterotopic ossification in muscle tissues. Constitutively activated mutants of a bone morphogenetic protein (BMP) receptor, ALK2, have been identified in patients with FOP. Recently, a novel ALK2 mutation, L196P, was found in the most benign case of FOP reported thus far. In the present study, we examined the biological activities of ALK2(L196P) in vitro. Over-expression of ALK2(L196P) induced BMP-specific activities, including the suppression of myogenesis, the induction of alkaline phosphatase activity, increased BMP-specific luciferase reporter activity, and increased phosphorylation of Smad1/5 but not Erk1/2 or p38. The activities of ALK2(L196P) were higher than those of ALK2(G356D), another mutant ALK2 allele found in patients with FOP and were equivalent to those of ALK2(R206H), a typical mutation found in patients with FOP. ALK2(L196P) was equally or more resistant to inhibitors in comparison to ALK2(R206H). These findings suggest that ALK2(L196P) is an activated BMP receptor equivalent to ALK2(R206H) and that ALK2(L196P) activity may be suppressed in vivo by a novel molecular mechanism in patients with this mutation.",
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T1 - A novel mutation of ALK2, L196P, found in the most benign case of fibrodysplasia ossificans progressiva activates BMP-specific intracellular signaling equivalent to a typical mutation, R206H

AU - Ohte, Satoshi

AU - Shin, Masashi

AU - Sasanuma, Hiroki

AU - Yoneyama, Katsumi

AU - Akita, Masumi

AU - Ikebuchi, Kenji

AU - Jimi, Eijiro

AU - Maruki, Yuichi

AU - Matsuoka, Masaru

AU - Namba, Akira

AU - Tomoda, Hiroshi

AU - Okazaki, Yasushi

AU - Ohtake, Akira

AU - Oda, Hiromi

AU - Owan, Ichiro

AU - Yoda, Tetsuya

AU - Furuya, Hirokazu

AU - Kamizono, Jyunji

AU - Kitoh, Hiroshi

AU - Nakashima, Yasuharu

AU - Susami, Takafumi

AU - Haga, Nobuhiko

AU - Komori, Tetsuo

AU - Katagiri, Takenobu

PY - 2011/4/1

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N2 - Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant congenital disorder characterized by progressive heterotopic ossification in muscle tissues. Constitutively activated mutants of a bone morphogenetic protein (BMP) receptor, ALK2, have been identified in patients with FOP. Recently, a novel ALK2 mutation, L196P, was found in the most benign case of FOP reported thus far. In the present study, we examined the biological activities of ALK2(L196P) in vitro. Over-expression of ALK2(L196P) induced BMP-specific activities, including the suppression of myogenesis, the induction of alkaline phosphatase activity, increased BMP-specific luciferase reporter activity, and increased phosphorylation of Smad1/5 but not Erk1/2 or p38. The activities of ALK2(L196P) were higher than those of ALK2(G356D), another mutant ALK2 allele found in patients with FOP and were equivalent to those of ALK2(R206H), a typical mutation found in patients with FOP. ALK2(L196P) was equally or more resistant to inhibitors in comparison to ALK2(R206H). These findings suggest that ALK2(L196P) is an activated BMP receptor equivalent to ALK2(R206H) and that ALK2(L196P) activity may be suppressed in vivo by a novel molecular mechanism in patients with this mutation.

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