Somatic activating mutations in MAP2K1 cause melorheostosis

Heeseog Kang, Smita Jha, Zuoming Deng, Nadja Fratzl-Zelman, Wayne A. Cabral, Aleksandra Ivovic, Françoise Meylan, Eric P. Hanson, Eileen Lange, James Katz, Paul Roschger, Klaus Klaushofer, Edward W. Cowen, Richard M. Siegel, Joan C. Marini and Timothy Bhattacharyya ()
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Heeseog Kang: National Institutes of Health
Smita Jha: National Institutes of Health
Zuoming Deng: National Institutes of Health
Nadja Fratzl-Zelman: 1st Medical Department Hanusch Hospital, UKH Meidling
Wayne A. Cabral: National Institutes of Health
Aleksandra Ivovic: National Institutes of Health
Françoise Meylan: National Institutes of Health
Eric P. Hanson: National Institutes of Health
Eileen Lange: National Institutes of Health
James Katz: National Institutes of Health
Paul Roschger: 1st Medical Department Hanusch Hospital, UKH Meidling
Klaus Klaushofer: 1st Medical Department Hanusch Hospital, UKH Meidling
Edward W. Cowen: National Institutes of Health
Richard M. Siegel: National Institutes of Health
Joan C. Marini: National Institutes of Health
Timothy Bhattacharyya: National Institutes of Health

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-03720-z

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