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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.
Biochem Biophys Res Commun. 2011 Apr 01; 407(1):213-8.BB

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.

Authors+Show Affiliations

Division of Pathophysiology, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21377447

Citation

Ohte, Satoshi, et al. "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, vol. 407, no. 1, 2011, pp. 213-8.
Ohte S, Shin M, Sasanuma H, et al. 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. Biochem Biophys Res Commun. 2011;407(1):213-8.
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., ... 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, 407(1), 213-8. https://doi.org/10.1016/j.bbrc.2011.03.001
Ohte S, et al. 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. Biochem Biophys Res Commun. 2011 Apr 1;407(1):213-8. PubMed PMID: 21377447.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR 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, Y1 - 2011/03/04/ PY - 2011/02/28/received PY - 2011/03/01/accepted PY - 2011/3/8/entrez PY - 2011/3/8/pubmed PY - 2011/6/1/medline SP - 213 EP - 8 JF - Biochemical and biophysical research communications JO - Biochem Biophys Res Commun VL - 407 IS - 1 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. SN - 1090-2104 UR - https://www.unboundmedicine.com/medline/citation/21377447/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_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-291X(11)00362-7 DB - PRIME DP - Unbound Medicine ER -