Somatic activating mutations in MAP2K1 cause melorheostosis

Authors

• H Kang
• S Jha
• Z Deng
• N Fratzl-Zelman
• WA Cabral
• A Ivovic
• F Meylan
• EP Hanson
• E Lange
• J Katz
• P Roschger
• K Klaushofer
• EW Cowen
• RM Siegel
• JC Marini
• T Bhattacharyya

Abstract

Melorhesotosis is a rare condition of excess bone formation for which there is no definitive diagnostic test, and the causative gene was unknown. X-rays of patients have a distinctive appearance of “dripping candle wax” on the surface of cortical bone. The bone overgrowth lesions are associated with pain, deformity, and functional impairment. Because no cases of vertical transmission in families were reported, we hypothesized that somatic mutations in the lesions would be causative. Our goal was to examine bone lesions directly for potential somatic mutations associated with development of melorheostosis. To obtain samples, we recruited 15 unrelated melorheostosis patients, who underwent paired biopsies of affected and contralateral unaffected bone for DNA extraction and whole exome sequencing. By comparing the paired samples of each patient, we identified somatic mosaic mutations in MAP2K1, encoding Mitogen-Activated Protein Kinase Kinase 1 (MEK1), in DNA from affected, but not unaffected bone, of 8 of 15 patients. The lesions occur at a hotspot (p.Q56P, p.K57E, and p.K57N) located within the negative regulatory domain of MEK1, and were previously identified in various malignancies. Mosaicism was demonstrated by immunohistochemical analysis of ERK1/2 (phos-ERK1/2) activation in affected bone and as two populations with distinct phos-ERK1/2 levels in flow cytometry of affected osteoblasts. Histology of melorheostotic bone revealed two regions: an outer region composed of distinctive parallel layers of primary lamellar bone, and an inner region of intense bone remodeling with increased osteoblasts and osteoclasts. Functional studies of patient affected osteoblasts revealed enhanced cell proliferation with increased cyclin D expression. Paradoxically, the activating MAP2K1 mutations suppressed BMP2-mediated osteoblast differentiation and matrix mineralization in culture, explaining the significantly increased unmineralized osteoid seen in affected bone histology. The immature affected osteoblasts have a higher ratio of RANKL to OPG, which indicates increased osteoclastogenesis by mutant osteoblasts in melorheostotic bone. This study uncovered a new role for the MAP2K1 oncogene in human bone formation. This suggests that MEK1 inhibition, which is already in trials for cancer, may be a good therapeutic candidate for melorheostosis treatment.

Scientific Focus Area: Genetics and Genomics

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