Frequent phosphodiesterase 11A gene (PDE11A) defects in patients with Carney complex (CNC) caused by PRKAR1A mutations: PDE11A may contribute to adrenal and testicular tumors in CNC as a modifier of the phenotype.

Abstract

BACKGROUND:

Carney complex (CNC) is an autosomal dominant multiple neoplasia, caused mostly by inactivating mutations of the regulatory subunit 1A of the protein kinase A (PRKAR1A). Primary pigmented nodular adrenocortical disease (PPNAD) is the most frequent endocrine manifestation of CNC with a great inter-individual variability. Germline, protein-truncating mutations of phosphodiesterase type 11A (PDE11A) have been described to predispose to a variety of endocrine tumors, including adrenal and testicular tumors.

OBJECTIVES:

Our objective was to investigate the role of PDE11A as a possible gene modifier of the phenotype in a series of 150 patients with CNC.

RESULTS:

A higher frequency of PDE11A variants in patients with CNC compared with healthy controls was found (25.3 vs. 6.8%, P < 0.0001). Among CNC patients, those with PPNAD were significantly more frequently carriers of PDE11A variants compared with patients without PPNAD (30.8 vs. 13%, P = 0.025). Furthermore, men with PPNAD were significantly more frequently carriers of PDE11A sequence variants (40.7%) than women with PPNAD (27.3%) (P < 0.001). A higher frequency of PDE11A sequence variants was also found in patients with large-cell calcifying Sertoli cell tumors (LCCSCT) compared with those without LCCSCT (50 vs. 10%, P = 0.0056). PDE11A variants were significantly associated with the copresence of PPNAD and LCCSCT in men: 81 vs. 20%, P < 0.004). The simultaneous inactivation of PRKAR1A and PDE11A by small inhibitory RNA led to an increase in cAMP-regulatory element-mediated transcriptional activity under basal conditions and after stimulation by forskolin.

CONCLUSIONS:

We demonstrate, in a large cohort of CNC patients, a high frequency of PDE11A variants, suggesting that PDE11A is a genetic modifying factor for the development of testicular and adrenal tumors in patients with germline PRKAR1A mutation.

• Authors: Rossella Libé, Anelia Horvath, Delphine Vezzosi, Amato Fratticci, Joel Coste, Karine Perlemoine, Bruno Ragazzon, Marine Guillaud-Bataille, Lionel Groussin, Eric Clauser, Marie-Laure Raffin-Sanson, Jennifer Siegel, Jason Moran, Limor Drori-Herishanu, Fabio Rueda Faucz, Maya Lodish, Maria Nesterova, Xavier Bertagna, Jerome Bertherat, Constantine A Stratakis
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 96 Issue 1 Pg. E208-14 (Jan 2011) ISSN: 1945-7197 [Electronic] United States
• PMID: 21047926 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cyclic AMP-Dependent Protein Kinase RIalpha Subunit
• PRKAR1A protein, human
• RNA, Small Interfering
• Phosphoric Diester Hydrolases
• 3',5'-Cyclic-GMP Phosphodiesterases
• PDE11A protein, human

Topics

• 3',5'-Cyclic-GMP Phosphodiesterases
• Adolescent
• Adrenal Gland Neoplasms (genetics)
• Adult
• Carney Complex (genetics)
• Child
• Child, Preschool
• Cyclic AMP-Dependent Protein Kinase RIalpha Subunit (genetics)
• Female
• Genetic Variation
• HEK293 Cells
• Humans
• Male
• Middle Aged
• Mutation
• Phenotype
• Phosphoric Diester Hydrolases (genetics)
• RNA, Small Interfering
• Sertoli Cell Tumor (genetics)
• Sex Factors
• Testicular Neoplasms (genetics)