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 |
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| Authors: | 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 Nakashima Takafumi Susami Nobuhiko Haga Tetsuo Komori Takenobu Katagiri |
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| Institution: | aDivision of Pathophysiology, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241, Japan;bProject of Clinical and Basic Research for FOP at Saitama Medical University, Japan;cDivision of Morphological Science, Biomedical Research Center, Saitama Medical University, 38 Moro Hongo, Moroyama-machi, Iruma-gun, Saitama 350-0495, Japan;dDivision of Laboratory Medicine, Saitama Medical University, 38 Moro Hongo, Moroyama-machi, Iruma-gun, Saitama 350-0495, Japan;eDivision of Molecular Signaling and Biochemistry, Department of Biosciences, Kyushu Dental Collage, 2-6-1Manazuru, Kokurakita-ku, Kitakyushu-shi, Fukuoka 803-8580, Japan;fDepartment of Neurology, Saitama Neuropsychiatric Institute, 6-11-1 Honchohigashi, Chuo-ku, Saitama-shi, Saitama 338-8577, Japan;gDivision of Obstetrics and Gynecology, Saitama Medical University, 38 Moro Hongo, Moroyama-machi, Iruma-gun, Saitama 350-0495, Japan;hGraduate School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-0023, Japan;iDivision of Functional Genomics & Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama 350-1241, Japan;jDivision of Pediatrics, Saitama Medical University, 38 Moro Hongo, Moroyama-machi, Iruma-gun, Saitama 350-0495, Japan;kDivision of Orthopedic Surgery, Saitama Medical University, 38 Moro Hongo, Moroyama-machi, Iruma-gun, Saitama 350-0495, Japan;lDepartment of Orthopedic Surgery, University of Ryukyus Faculty of Medicine, 207 Uehara, Nishihara-cho, Okinawa 903-0215, Japan;mDivision of Oral and Maxillofacial Surgery, Saitama Medical University, 38 Moro Hongo, Moroyama-machi, Iruma-gun, Saitama 350-0495, Japan;nDepartment of Neurology, Neuro-Muscular center, National Omuta Hospital, Tachibana 1044-1, Omuta, Fukuoka 837-0911, Japan;oThe Research Committee on Fibrodysplasia Ossificans Progressiva of the Ministry of Health, Labour and Welfare, Japan;pKitakyushu City Yahata Hospital Pediatric Emergency Department, 4-18-1 Nishihon-machi, Yahatahigashi-ku, Kitakyushu-shi, Fukuoka 805-0061, Japan;qDepartment of Orthopedic Surgery, Graduate School of Medicine, Nagoya University, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan;rDepartment of Orthopaedic Surgery, Faculty of Medicine, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka-shi, Fukuoka 812-8582, Japan;sDepartment of Oral-Maxillofacial Surgery, Dentistry and Orthodontics, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan;tDepartment of Rehabilitation Medicine, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan;uDepartment of Neurology, National Hakone Hospital, 412 Kazamatsuri, Odawara-shi, Kanagawa 250-0032, Japan |
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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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| Keywords: | FOP ALK2 BMP Smad Muscle Signaling |
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