ClinVar

In samples of affected bone from 4 patients (Melo-2, Melo-6, Melo-16, and Melo-18) with melorheostosis (MEL; 155950), Kang et al. (2018) identified somatic mosaicism for a c.171G-T transversion (c.171G-T, NM_002755) in exon 2 of the MAP2K1 gene, resulting in a lys57-to-asn (K57N) substitution within the alpha-helix of the negative regulatory domain. Mutant allele frequency ranged from 3 to 34% in affected bone; the variant was not found in unaffected bone or in peripheral blood leukocytes, or in the ExAC database. Analysis of overlying skin in 3 of the patients showed the variant at an allele frequency of 4.1 to 16.2%; the variant was not detected in skin from patient Melo-16, who had a lower disease burden. Western blot analysis of cultured patient osteoblasts showed increased phosphorylation of MAP2K1 target kinases ERK1 (MAPK3; 601795) and ERK2 (MAPK1; 176948) compared to cells from unaffected bone, confirming a gain-of-function effect with the K57N variant, and the level of ERK1/2 activation by MEK1 generally correlated with mutant allele frequency. Consistent with enhanced activation, affected osteoblasts showed increased cell proliferation in vitro; however, there was also reduced mineralization and differentiation with affected osteoblasts, as well as increased osteoclast activity.