Publication
Title
A multi-omics approach expands the mutational spectrum of MAP2K1-related melorheostosis
Author
Abstract
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 a 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 a 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 a 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.
Language
English
Source (journal)
Bone / International Bone and Mineral Society. - New York
Publication
New York : 2020
ISSN
8756-3282
DOI
10.1016/J.BONE.2020.115406
Volume/pages
137 (2020) , p. 1-8
Article Reference
UNSP 115406
ISI
000547005800024
Pubmed ID
32387835
Medium
E-only publicatie
Full text (Publisher's DOI)
Full text (publisher's version - intranet only)
UAntwerpen
Faculty/Department
Research group
Project info
Systems biology for the functional validation of genetic determinants of skeletal diseases (SYBIL).
Paget's disease of bone: molecular genetic investigation of the NFkB signaling regulating genes CBL, CBLB, and NR4A1 and functional validation in vitro and in Danio rerio.
Identification of pan-cancer and tumor-specific methylation based biomarkers and development of bioinformatics infrastructure for a novel multiplex methylation assay.
Evaluation of the role of LRP4 in the regulation of Wnt/Bcatenin dependent Wnt signalling and bone formation.
GENOMED - Genomics in Medicine.
Publication type
Subject
Affiliation
Publications with a UAntwerp address
External links
Web of Science
Record
Identifier
Creation 20.08.2020
Last edited 12.12.2024
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