PRKACA defects and adrenal tumors: Animal studies and gene dosage effects

Authors

• P Salpea
• A Angelousi
• B Yuan
• FR Faucz
• I Levy
• B Delemer
• S Hieronimus
• B Feve
• F Kelestimur
• G Raverot
• J Bertherat
• JR Lupski
• M Serpe
• CA Stratakis

Abstract

Genetic defects that cause abnormal c-AMP dependent Protein Kinase A (PKA) signaling constitute the leading cause for adrenal tumors and ACTH-independent Cushing syndrome (CS). Recently two types of activating defects of the PKA catalytic subunit gene (PRKACA) were described leading to abnormal PKA signaling and adrenal tumors. Interestingly, adrenal disease due to PRKACA activating defects appears to correlate with PRKACA gene dosage and function of the catalytic subunit. We chose the D. melanogaster model to test the dosage-dependent effect of PRKACA. Previous studies described hypomorphic alleles of the PKA system in flies. We created transgenic flies carrying the various types of PKA main catalytic subunit (PKA-C1) activating defects we detected in our patient cohort. The first type of fly contained one additional copy of the PKA-C1, these flies had elevated PKA activity but no apparent phenotypic defects. The introduction of two extra PKA-C1 copies led to phenotypic defects. The second type of transgenic fly had a constitutively active PKA-C1 (PKA-act) specifically in the prothoracic gland (PG). This highly increased PKA activity in the PG (phm>PKA-act) effectively blocked the onset of pupariation due to decreased production and/or release of ecdysone, a hormone that controls developmental timing in insects. Our animal model studies with the human genetics data showed that the dose of PKA main catalytic subunit correlates with the type of adrenal disease and developmental defects in a dose-dependent manner.

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