Cushing's Syndrome and Fetal Features Resurgence in Adrenal Cortex–Specific Prkar1a Knockout Mice

Isabelle Sahut-Barnola,Isabelle Sahut-Barnola,Isabelle Sahut-Barnola,Geoffroy Marceau,Geoffroy Marceau,Geoffroy Marceau,Christelle Damon,Antoine Martinez,Antoine Martinez,Antoine Martinez,Bruno Ragazzon,Bruno Ragazzon,Bruno Ragazzon,Bruno Ragazzon,Bruno Ragazzon,Bruno Ragazzon,Jérôme Bertherat,Jérôme Bertherat,Jérôme Bertherat,Jérôme Bertherat,Jérôme Bertherat,Jérôme Bertherat,Frédérique Tissier,Frédérique Tissier,Frédérique Tissier,Frédérique Tissier,Frédérique Tissier,Frédérique Tissier,Vincent Sapin,Vincent Sapin,Vincent Sapin,Jean-Christophe Pointud,Jean-Christophe Pointud,Jean-Christophe Pointud,Cyrille De Joussineau,Cyrille De Joussineau,Cyrille De Joussineau,Sarah Lambert-Langlais,Sarah Lambert-Langlais,Sarah Lambert-Langlais,Pierre Val,Pierre Val,Pierre Val,Lawrence S Kirschner,Constantine A Stratakis,Anne-Marie Lefrançois-Martinez,Anne-Marie Lefrançois-Martinez,Anne-Marie Lefrançois-Martinez

doi:10.1371/journal.pgen.1000980

Abstract

Carney complex (CNC) is an inherited neoplasia syndrome with endocrine overactivity. Its most frequent endocrine manifestation is primary pigmented nodular adrenocortical disease (PPNAD), a bilateral adrenocortical hyperplasia causing pituitary-independent Cushing's syndrome. Inactivating mutations in PRKAR1A, a gene encoding the type 1 α-regulatory subunit (R1α) of the cAMP–dependent protein kinase (PKA) have been found in 80% of CNC patients with Cushing's syndrome. To demonstrate the implication of R1α loss in the initiation and development of PPNAD, we generated mice lacking Prkar1a specifically in the adrenal cortex (AdKO). AdKO mice develop pituitary-independent Cushing's syndrome with increased PKA activity. This leads to autonomous steroidogenic genes expression and deregulated adreno-cortical cells differentiation, increased proliferation and resistance to apoptosis. Unexpectedly, R1α loss results in improper maintenance and centrifugal expansion of cortisol-producing fetal adrenocortical cells with concomitant regression of adult cortex. Our data provide the first in vivo evidence that loss of R1α is sufficient to induce autonomous adrenal hyper-activity and bilateral hyperplasia, both observed in human PPNAD. Furthermore, this model demonstrates that deregulated PKA activity favors the emergence of a new cell population potentially arising from the fetal adrenal, giving new insight into the mechanisms leading to PPNAD.

Highlights

Primary pigmented nodular adrenocortical disease (PPNAD) is a rare form of bilateral micronodular adrenocortical hyperplasia leading to high morbidity due to ACTH-independent Cushing’s syndrome
The 60% loss of regulatory subunit 1a (R1a) protein in adrenal tissue lysate of Adrenal cortex-specific Prkar1a knockout mice (AdKO) mice was accompanied by a significant increase in accumulation of R2b and C protein kinase (PKA) subunits (Figure 1C), a phenomenon that is observed in PPNAD [8]
We shown that the adrenal-specific ablation of Prkar1a, the Carney Complex gene 1 (CNC1), in mouse reproduced the essential features of PPNAD observed in humans carrying PRKAR1A mutations

Summary

Introduction

Primary pigmented nodular adrenocortical disease (PPNAD) is a rare form of bilateral micronodular adrenocortical hyperplasia leading to high morbidity due to ACTH (adreno corticotropic hormone)-independent Cushing’s syndrome. PPNAD may be either sporadic or regarded as the most frequent endocrine manifestation of Carney complex (CNC), an autosomal dominant multiple neoplasia syndrome characterized by cardiac myxomas, spotty skin pigmentation and endocrine overactivity [1]. Cushing’s syndrome in PPNAD is most diagnosed in children and young adults. Both isolated PPNAD and CNC have been associated with inactivating mutations in PRKAR1A, the gene encoding the type 1a regulatory subunit (R1a) of the cAMP-dependent protein kinase (PKA) [2,3]. Among CNC patients with Cushing’s syndrome, the frequency of PRKAR1A mutations is about 80%. Tumour-specific loss of heterozygosity within the chromosomal region harboring

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Conclusion