Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UNIPROT:P50583 (
asymmetrical
)
12,197
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Melorheostosis
is a very rare sclerosing bone dysplasia characterized by
asymmetrical
and progressive cortical hyperostosis, usually with involvement of soft tissues surrounding the lesions. Recently Kang et al. identified somatic mosaicism for variants (p.Gln56Pro, p.Lys57Asn, or p.Lys57Glu) in the negative regulatory domain of MAP2K1, resulting in increased ERK1/2 signalling in affected tissues. In our study, we employed several sequencing technologies to unravel genetic variants (only present in affected tissues) from four sporadic
melorheostosis
patients. In the exome of two patients, we identified the same variants (p.K57N and p.K57E) as previously described by Kang et al. WGS and RNAseq analysis in a third patient demonstrated the presence of a novel variant (p.Cys121Ser) in the catalytic domain of MAP2K1. In addition, gene set enrichment analysis of the transcriptome data demonstrated upregulation of proliferative pathways. Interestingly, increased proliferation of MAP2K1 p.Lys57Asn-positive osteoblasts has been reported by Kang et al. The variants located in the hotspot region of the negative regulatory domain as well as this newly identified p.Cys121Ser variant have all been classified as MAP2K1 variants that can constitutively activate the downstream effector Erk. Finally, in a fourth patient with classical radiographic features of
melorheostosis
, no pathogenic variants could be identified in MAP2K1 or the other candidate genes for
melorheostosis
(SMAD3; LEMD3; KRAS). In conclusion, our study strongly suggests that not only somatic variants in the regulatory domain of MAP2K1 but also in the catalytic domain can cause
melorheostosis
. Our observations confirm that mutations in MAP2K1 are a major cause of
melorheostosis
and also suggest further locus heterogeneity for this disorder.
...
PMID:A multi-omics approach expands the mutational spectrum of MAP2K1-related melorheostosis. 3238 35
