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.
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.


OBJECTIVE
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.
Institut National de la Santé et de la Recherche Médicale Unité 1016, Institut Cochin, Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Paris, France.
Rossella
R
Libé
Anelia
A
Horvath
Delphine
D
Vezzosi
Amato
A
Fratticci
Joel
J
Coste
Karine
K
Perlemoine
Bruno
B
Ragazzon
Marine
M
Guillaud-Bataille
Lionel
L
Groussin
Eric
E
Clauser
Marie-Laure
ML
Raffin-Sanson
Jennifer
J
Siegel
Jason
J
Moran
Limor
L
Drori-Herishanu
Fabio Rueda
FR
Faucz
Maya
M
Lodish
Maria
M
Nesterova
Xavier
X
Bertagna
Jerome
J
Bertherat
Constantine A
CA
Stratakis
D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000293:Adolescent; D000310:Adrenal Gland Neoplasms / Q000235:genetics*; D000328:Adult; D056733:Carney Complex / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D010727:Phosphoric Diester Hydrolases / Q000235:genetics*; D034741:RNA, Small Interfering; D012707:Sertoli Cell Tumor / Q000235:genetics*; D012737:Sex Factors; D013736:Testicular Neoplasms / Q000235:genetics*
D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; C517834:PRKAR1A protein, human; D034741:RNA, Small Interfering; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; C406737:PDE11A protein, human