A Mosaic Variant in CTNNB1/β-catenin as a Novel Cause for Osteopathia Striata With Cranial Sclerosis

In conclusion, this study indicates that somatic variants in the CTNNB1 gene could explain the pathogenesis of unsolved cases of osteopathia striata.

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.

Whole exome sequencing led to the identification of a mosaic missense variant (c.876A > C; p.Lys292Asn) in CTNNB1, coding for β-catenin. The variant disrupts an amino acid known to be crucial for interaction with AXIN, a key factor in the β-catenin destruction complex. Western blotting experiments demonstrate that the p.Lys292Asn variant does not significantly affect the β-catenin phosphorylation status, and hence stability in the cytoplasm. Additionally, luciferase reporter assays were performed to investigate the effect of p.Lys292Asn β-catenin on canonical WNT signaling. These studies indicate an average 70-fold increase in canonical WNT signaling activity by p.Lys292Asn β-catenin.