LEM domain-containing protein 3 (LEMD3) gene mutations have been demonstrated in several familial cases, but these have been more strongly correlated with other hereditary dysplasias, such as osteopoikilosis, and are not thought to be the causative gene for melorheostosis.
Perhaps unsurprisingly in what is a segmental disease, we did not find LEMD3 mutations in peripheral-blood-derived DNA from the two other individuals with sporadic melorheostosis.
Perhaps unsurprisingly in what is a segmental disease, we did not find LEMD3 mutations in peripheral-blood-derived DNA from the two other individuals with sporadic melorheostosis.
However, LEMD3 germline mutations were only found in two melorheostosis patients belonging to a different BOS family and one sporadic patient with melorheostosis.
Somatic mosaicism for a LEMD3 mutation in the latter group was also not observed, and therefore we must conclude that the genetic defect in the majority of sporadic and isolated melorheostosis remains unknown.
A somatic mutation in the second allele of LEMD3could not be identified in fibroblasts from affected skin of an individual with BOS and an individual with melorheostosis.
Recent studies of melorheostosis lesional tissue indicate that most cases arise from somatic MAP2K1 mutations although a small number may arise from other genes in related pathways, such as KRAS.
The identification of a distinct phenotype of patients with MAP2K1-positive melorheostosis demonstrates clinical and genetic heterogeneity among patients with the disease.
Our data show that the MAP2K1 oncogene is important in human bone formation and implicate MEK1 inhibition as a potential treatment avenue for melorheostosis.
We report a patient with melorheostosis in whom increased procollagen alpha1(I) mRNA expression and alpha1(I), alpha2(I) and alpha1(III) collagen secretion were observed in dermal fibroblasts obtained from a skin biopsy overlying the involved bone.