Somatic activating mutations in MAP2K1 cause melorheostosis

• Published in: Nature communications Vol. 9; no. 1; pp. 1390 - 12
• Main Authors: Kang, Heeseog, Jha, Smita, Deng, Zuoming, Fratzl-Zelman, Nadja, Cabral, Wayne A., Ivovic, Aleksandra, Meylan, Françoise, Hanson, Eric P., Lange, Eileen, Katz, James, Roschger, Paul, Klaushofer, Klaus, Cowen, Edward W., Siegel, Richard M., Marini, Joan C., Bhattacharyya, Timothy
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11.04.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/106; 13/31; 13/51; 45; 45/23; 45/43; 631/208/2489/144; 631/80/304; 692/699/2743; Biocompatibility; Biomedical materials; Bone and Bones - metabolism; Bone and Bones - pathology; Bone growth; Bone lesions; Bone morphogenetic protein 2; Bone Morphogenetic Protein 2 - genetics; Bone Morphogenetic Protein 2 - metabolism; Calcification, Physiologic; Cell activation; Cell Differentiation; Cell Proliferation; Cytometry; Etiology; Exome Sequencing; Flow cytometry; Gene Expression Regulation; Histology; Humanities and Social Sciences; Humans; Immunohistochemistry; Lesions; MAP Kinase Kinase 1 - genetics; MAP Kinase Kinase 1 - metabolism; Melorheostosis; Melorheostosis - genetics; Melorheostosis - metabolism; Melorheostosis - pathology; Mineralization; Mitogen-Activated Protein Kinase 1 - genetics; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - genetics; Mitogen-Activated Protein Kinase 3 - metabolism; Mosaicism; multidisciplinary; Mutation; Osteoblastogenesis; Osteoblasts; Osteoblasts - metabolism; Osteoblasts - pathology; Osteogenesis; Osteogenesis - genetics; Osteoid; Patients; Primary Cell Culture; Science; Science (multidisciplinary); Signal Transduction; Skin - metabolism; Skin - pathology; Skin diseases; Therapeutic applications
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-03720-z

Melorheostosis is a sporadic disease of uncertain etiology characterized by asymmetric bone overgrowth and functional impairment. Using whole exome sequencing, we identify somatic mosaic MAP2K1 mutations in affected, but not unaffected, bone of eight unrelated patients with melorheostosis. The activating mutations (Q56P, K57E and K57N) cluster tightly in the MEK1 negative regulatory domain. Affected bone displays a mosaic pattern of increased p-ERK1/2 in osteoblast immunohistochemistry. Osteoblasts cultured from affected bone comprise two populations with distinct p-ERK1/2 levels by flow cytometry, enhanced ERK1/2 activation, and increased cell proliferation. However, these MAP2K1 mutations inhibit BMP2-mediated osteoblast mineralization and differentiation in vitro, underlying the markedly increased osteoid detected in affected bone histology. Mosaicism is also detected in the skin overlying bone lesions in four of five patients tested. Our data show that the MAP2K1 oncogene is important in human bone formation and implicate MEK1 inhibition as a potential treatment avenue for melorheostosis. Melorheostosis is characterized by bone overgrowth and associated with pain and functional impairment. Here, the authors use whole exome sequencing to identify somatic mutations in MAP2K1 in affected bone of melorheostosis patients which is associated with increased proliferation but delayed differentiation of cultured osteoblasts.