Publication
Title
A mosaic variant in CTNNB1/β-catenin as a novel cause for osteopathia striata with cranial sclerosis
Author
Abstract
Context: Osteopathia striata with cranial sclerosis (OSCS) is a rare bone disorder with X-linked dominant inheritance, characterized by a generalized hyperostosis in the skull and long bones and typical metaphyseal striations in the long bones. So far, loss-of-function variants in AMER1 (also known as WTX or FAM123B), encoding the APC membrane recruitment protein 1 (AMER1), have been described as the only molecular cause for OSCS. AMER1 promotes the degradation of beta-catenin via AXIN stabilization, acting as a negative regulator of the WNT/beta-catenin signaling pathway, a central pathway in bone formation.Objective: In this study, we describe a Dutch adult woman with an OSCS-like phenotype, namely, generalized high bone mass and characteristic metaphyseal striations, but no genetic variant affecting AMER1.Results: Whole exome sequencing led to the identification of a mosaic missense variant (c.876A > C; p.Lys292Asn) in CTNNB1, coding for beta-catenin. The variant disrupts an amino acid known to be crucial for interaction with AXIN, a key factor in the beta-catenin destruction complex. Western blotting experiments demonstrate that the p.Lys292Asn variant does not significantly affect the beta-catenin phosphorylation status, and hence stability in the cytoplasm. Additionally, luciferase reporter assays were performed to investigate the effect of p.Lys292Asn beta-catenin on canonical WNT signaling. These studies indicate an average 70-fold increase in canonical WNT signaling activity by p.Lys292Asn beta-catenin.Conclusion: In conclusion, this study indicates that somatic variants in the CTNNB1 gene could explain the pathogenesis of unsolved cases of osteopathia striata.
Language
English
Source (journal)
The journal of clinical endocrinology and metabolism. - Baltimore, Md
Publication
Washington : Endocrine soc , 2024
ISSN
0021-972X
DOI
10.1210/CLINEM/DGAD757
Volume/pages
(2024) , p. 1-8
ISI
001138679900001
Pubmed ID
38173341
Full text (Publisher's DOI)
Full text (publisher's version - intranet only)
UAntwerpen
Faculty/Department
Research group
Publication type
Subject
Affiliation
Publications with a UAntwerp address
External links
Web of Science
Record
Identifier
Creation 01.02.2024
Last edited 08.02.2024
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