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Molecular consequences of the ACVR1(R206H) mutation of fibrodysplasia ossificans progressiva.
J Biol Chem. 2010 Jul 16; 285(29):22542-53.JB

Abstract

Fibrodysplasia ossificans progressiva (FOP), a rare genetic and catastrophic disorder characterized by progressive heterotopic ossification, is caused by a point mutation, c.617G>A; p.R206H, in the activin A receptor type 1 (ACVR1) gene, one of the bone morphogenetic protein type I receptors (BMPR-Is). Although altered BMP signaling has been suggested to explain the pathogenesis, the molecular consequences of this mutation are still elusive. Here we studied the impact of ACVR1 R206H mutation on BMP signaling and its downstream signaling cascades in murine myogenic C2C12 cells and HEK 293 cells. We found that ACVR1 was the most abundant of the BMPR-Is expressed in mesenchymal cells but its contribution to osteogenic BMP signal transduction was minor. The R206H mutant caused weak activation of the BMP signaling pathway, unlike the Q207D mutant, a strong and constitutively active form. The R206H mutant showed a decreased binding affinity for FKBP1A/FKBP12, a known safeguard molecule against the leakage of transforming growth factor (TGF)-beta or BMP signaling. The decreased binding affinity of FKBP1A to the mutant R206H ACVR1 resulted in leaky activation of the BMP signal, and moreover, it decreased steady-state R206H ACVR1 protein levels. Interestingly, while WT ACVR1 and FKBP1A were broadly distributed in plasma membrane and cytoplasm without BMP-2 stimulation and then localized in plasma membrane on BMP-2 stimulation, R206H ACVR1 and FKBP1A were mainly distributed in plasma membrane regardless of BMP-2 stimulation. The impaired binding to FKBP1A and an altered subcellular distribution by R206H ACVR1 mutation may result in mild activation of osteogenic BMP-signaling in extraskeletal sites such as muscle, which eventually lead to delayed and progressive ectopic bone formation in FOP patients.

Authors+Show Affiliations

Department of Molecular Genetics, BK21 Program, School of Dentistry and Dental Research Institute, Seoul National University, Seoul 110-749, Korea.No 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

20463014

Citation

Song, Gin-Ah, et al. "Molecular Consequences of the ACVR1(R206H) Mutation of Fibrodysplasia Ossificans Progressiva." The Journal of Biological Chemistry, vol. 285, no. 29, 2010, pp. 22542-53.
Song GA, Kim HJ, Woo KM, et al. Molecular consequences of the ACVR1(R206H) mutation of fibrodysplasia ossificans progressiva. J Biol Chem. 2010;285(29):22542-53.
Song, G. A., Kim, H. J., Woo, K. M., Baek, J. H., Kim, G. S., Choi, J. Y., & Ryoo, H. M. (2010). Molecular consequences of the ACVR1(R206H) mutation of fibrodysplasia ossificans progressiva. The Journal of Biological Chemistry, 285(29), 22542-53. https://doi.org/10.1074/jbc.M109.094557
Song GA, et al. Molecular Consequences of the ACVR1(R206H) Mutation of Fibrodysplasia Ossificans Progressiva. J Biol Chem. 2010 Jul 16;285(29):22542-53. PubMed PMID: 20463014.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Molecular consequences of the ACVR1(R206H) mutation of fibrodysplasia ossificans progressiva. AU - Song,Gin-Ah, AU - Kim,Hyun-Jung, AU - Woo,Kyung-Mi, AU - Baek,Jeong-Hwa, AU - Kim,Gwan-Shik, AU - Choi,Jin-Young, AU - Ryoo,Hyun-Mo, Y1 - 2010/05/12/ PY - 2010/5/14/entrez PY - 2010/5/14/pubmed PY - 2010/8/7/medline SP - 22542 EP - 53 JF - The Journal of biological chemistry JO - J Biol Chem VL - 285 IS - 29 N2 - Fibrodysplasia ossificans progressiva (FOP), a rare genetic and catastrophic disorder characterized by progressive heterotopic ossification, is caused by a point mutation, c.617G>A; p.R206H, in the activin A receptor type 1 (ACVR1) gene, one of the bone morphogenetic protein type I receptors (BMPR-Is). Although altered BMP signaling has been suggested to explain the pathogenesis, the molecular consequences of this mutation are still elusive. Here we studied the impact of ACVR1 R206H mutation on BMP signaling and its downstream signaling cascades in murine myogenic C2C12 cells and HEK 293 cells. We found that ACVR1 was the most abundant of the BMPR-Is expressed in mesenchymal cells but its contribution to osteogenic BMP signal transduction was minor. The R206H mutant caused weak activation of the BMP signaling pathway, unlike the Q207D mutant, a strong and constitutively active form. The R206H mutant showed a decreased binding affinity for FKBP1A/FKBP12, a known safeguard molecule against the leakage of transforming growth factor (TGF)-beta or BMP signaling. The decreased binding affinity of FKBP1A to the mutant R206H ACVR1 resulted in leaky activation of the BMP signal, and moreover, it decreased steady-state R206H ACVR1 protein levels. Interestingly, while WT ACVR1 and FKBP1A were broadly distributed in plasma membrane and cytoplasm without BMP-2 stimulation and then localized in plasma membrane on BMP-2 stimulation, R206H ACVR1 and FKBP1A were mainly distributed in plasma membrane regardless of BMP-2 stimulation. The impaired binding to FKBP1A and an altered subcellular distribution by R206H ACVR1 mutation may result in mild activation of osteogenic BMP-signaling in extraskeletal sites such as muscle, which eventually lead to delayed and progressive ectopic bone formation in FOP patients. SN - 1083-351X UR - https://www.unboundmedicine.com/medline/citation/20463014/Molecular_consequences_of_the_ACVR1_R206H__mutation_of_fibrodysplasia_ossificans_progressiva_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=20463014 DB - PRIME DP - Unbound Medicine ER -