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An Activating Variant in CTNNB1 is Associated with a Sclerosing Bone Dysplasia and Adrenocortical Neoplasia


CONTEXT: The WNT/beta-catenin pathway is central to the pathogenesis of various human diseases including those affecting bone development and tumor progression. OBJECTIVE: To evaluate the role of a gain-of-function variant in CTNNB1 in a child with a sclerosing bone dysplasia and an adrenocortical adenoma. DESIGN: Whole exome sequencing with corroborative biochemical analyses. PATIENTS: We recruited a child with a sclerosing bone dysplasia and an adrenocortical adenoma together with her unaffected parents. INTERVENTION: Whole exome sequencing and performance of immunoblotting and luciferase-based assays to assess the cellular consequences of a de novo variant in CTNNB1. MAIN OUTCOME MEASURE(S)/RESULT: A de novo variant in CTNNB1 (c.131C>T; p.[Pro44Leu]) was identified in a patient with a sclerosing bone dysplasia and an adrenocortical adenoma. A luciferase-based transcriptional assay of WNT signaling activity verified that the activity of beta-catenin was increased in the cells transfected with a CTNNB1p.Pro44Leu construct (P = 4.00 x 10-5). The beta-catenin p.Pro44Leu variant was also associated with a decrease in phosphorylation at Ser45 and Ser33/Ser37/Thr41 in comparison to a wild-type (WT) CTNNB1 construct (P = 2.16 x 10-3, P = 9.34 x 10-8 respectively). CONCLUSION: Increased beta-catenin activity associated with a de novo gain-of-function CTNNB1 variant is associated with osteosclerotic phenotype and adrenocortical neoplasia.

Type Journal
ISBN 1945-7197 (Electronic) 0021-972X (Linking)
Authors Peng, H.; Jenkins, Z. A.; White, R.; Connors, S.; Hunter, M. F.; Ronan, A.; Zankl, A.; Markie, D. M.; Daniel, P. B.; Robertson, S. P.
Responsible Garvan Author Prof Andreas Zankl
Published Date 2020-03-01
Published Volume 105
Published Issue 3
Status Published in-print
DOI 10.1210/clinem/dgaa034
URL link to publisher's version