PRKACB variants in skeletal disease or adrenocortical hyperplasia: effects on protein kinase A

in Endocrine-Related Cancer
Authors:
Stephanie Espiard Section on Endocrinology & Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA
Université de Paris, Cochin Institute, Inserm U1016, CNRS 8104, Paris, France

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Ludivine Drougat Section on Endocrinology & Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA

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Nikolaos Settas Section on Endocrinology & Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA

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Sara Haydar Section on Endocrinology & Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA

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Kerstin Bathon Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany

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Edra London Section on Endocrinology & Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA

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Isaac Levy Section on Endocrinology & Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA

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Fabio R Faucz Section on Endocrinology & Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA

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https://orcid.org/0000-0001-7959-9842
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Davide Calebiro Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK
Centre of Membrane Proteins and Receptors (COMPARE), Universities of Nottingham and Birmingham, Birmingham, UK

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Jérôme Bertherat Université de Paris, Cochin Institute, Inserm U1016, CNRS 8104, Paris, France
Center for Rare Adrenal Diseases, Endocrinology Department, Cochin Hospital, Assistance Publique Hôpitaux de Paris, Paris, France

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Dong Li Center for Applied Genomics at The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

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Michael A Levine Division of Endocrinology and Diabetes and The Center for Bone Health at The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA

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Constantine A Stratakis Section on Endocrinology & Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA

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Correspondence should be addressed to N Settas: nikolaos.settas@nih.gov
DOI:
https://doi.org/10.1530/ERC-20-0309
Volume/Issue:
Volume 27: Issue 11
Article Type:
Research Article
Page Range:
647–656
Online Publication Date:
Nov 2020
Copyright:
© 2020 Society for Endocrinology 2020
Restricted access
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Genetic variants in components of the protein kinase A (PKA) enzyme have been associated with various defects and neoplasms in the context of Carney complex (CNC) and in isolated cases, such as in primary pigmented nodular adrenocortical disease (PPNAD), cortisol-producing adrenal adenomas (CPAs), and various cancers. PRKAR1A mutations have been found in subjects with impaired cAMP-dependent signaling and skeletal defects; bone tumors also develop in both humans and mice with PKA abnormalities. We studied the PRKACB gene in 148 subjects with PPNAD and related disorders, who did not have other PKA-related defects and identified two subjects with possibly pathogenic PRKACB gene variants and unusual bone and endocrine phenotypes. The first presented with bone and other abnormalities and carried a de novo c.858_860GAA (p.K286del) variant. The second subject carried the c.899C>T (p.T300M or p.T347M in another isoform) variant and had a PPNAD-like phenotype. Both variants are highly conserved in the PRKACB gene. In functional studies, the p.K286del variant affected PRKACB protein stability and led to increased PKA signaling. The p.T300M variant did not affect protein stability or response to cAMP and its pathogenicity remains uncertain. We conclude that PRKACB germline variants are uncommon but may be associated with phenotypes that resemble those of other PKA-related defects. However, detailed investigation of each variant is needed as PRKACB appears to be only rarely affected in these conditions, and variants such as p.T300M maybe proven to be clinically insignificant, whereas others (such as p.K286del) are clearly pathogenic and may be responsible for a novel syndrome, associated with endocrine and skeletal abnormalities.

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Print ISSN:
1351-0088
Online ISSN:
1479-6821
Copyright:
© 2020 Society for Endocrinology 2020
Page(s):
10
Received Date:
21 Aug 2020
Accepted Date:
16 Sep 2020
Print Publication Date:
01 Nov 2020
Online Publication Date:
Nov 2020
Keywords:
cyclic AMP; cortisol; adrenocortical hyperplasia; PRKAR1A; PRKACA; PRKACB

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