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

Abstract

CONTEXT:

The WNT/β-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 β-catenin was increased in the cells transfected with a CTNNB1p.Pro44Leu construct (P = 4.00 × 10-5). The β-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 × 10-3, P = 9.34 × 10-8 respectively).

CONCLUSION:

Increased β-catenin activity associated with a de novo gain-of-function CTNNB1 variant is associated with osteosclerotic phenotype and adrenocortical neoplasia.

• Authors: Hui Peng, Zandra A Jenkins, Ruby White, Sam Connors, Matthew F Hunter, Anne Ronan, Andreas Zankl, David M Markie, Philip B Daniel, Stephen P Robertson
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 105 Issue 3 (03 01 2020) ISSN: 1945-7197 [Electronic] United States
• PMID: 31970420 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © Endocrine Society 2020. All rights reserved. For permissions, please e-mail: [email protected].

Chemical References

• CTNNB1 protein, human
• beta Catenin

Topics

• Adrenal Cortex Neoplasms (genetics, pathology)
• Adrenocortical Carcinoma (genetics, pathology)
• Bone Diseases, Developmental (genetics, pathology)
• Female
• Humans
• Infant, Newborn
• Male
• Mutation
• Pedigree
• Phenotype
• Prognosis
• Exome Sequencing
• beta Catenin (genetics)