Abnormalities of cAMP signaling are present in adrenocortical lesions associated with ACTH-independent Cushing syndrome despite the absence of mutations in known genes.
BACKGROUND
Bilateral adrenal hyperplasias (BAHs) may be caused by mutations of genes that code for molecules that participate in cAMP signaling. Little is known about cAMP signaling in adrenal lesions associated with ACTH-independent Cushing syndrome (AICS) that do not harbor mutations in known genes.


OBJECTIVE
We assessed the cAMP-signaling pathway by enzymatic and molecular studies.


METHODS
Samples from 27 patients (ages 5-60 years) were studied and compared with normal adrenocortical tissue (n=4) and aldosterone-producing adenomas (APA, n=5). All samples were sequenced for GNAS, PRKAR1A, PDE11A, and PDE8B sequencing defects. cAMP levels and binding, protein kinase A, and phosphodiesterase (PDE) activities were assayed. Immunohistochemistry was used for certain studies and the phosphorylation status of CREB was studied.


METHODS
A total of 36 samples from patients were used.


RESULTS
Cortisol-producing adenomas (CPAs) and other lesions that were GNAS, PRKAR1A, PDE11A, and PDE8B gene mutation-negative were compared with PRKAR1A mutation-positive lesions, normal tissue, and APAs; abnormalities of the cAMP-signaling pathway were found in both BAHs and CPAs. Interestingly, mutation-negative CPAs had significantly decreased PDE activity.


CONCLUSIONS
Lesions of the adrenal associated with AICS, independently of their GNAS, PRKAR1A, PDE11A, and PDE8B mutation status, have functional abnormalities of cAMP signaling. It is probable that epigenetic events or additional defects of genes involved in this pathway are responsible for this phenomenon.
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Building 10, CRC (East Laboratories), Room 1-3330, 10 Center Drive, MSC1103, Bethesda, Maryland 20892, USA.
Eirini I
EI
Bimpaki
Maria
M
Nesterova
Constantine A
CA
Stratakis
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000235:genetics; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000236:Adenoma / Q000235:genetics / Q000378:metabolism*; D000293:Adolescent; D000306:Adrenal Cortex Neoplasms / Q000235:genetics / Q000378:metabolism*; D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000328:Adult; D050882:CREB-Binding Protein / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D002864:Chromogranins; D003480:Cushing Syndrome / Q000235:genetics / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism*; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / Q000235:genetics; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010727:Phosphoric Diester Hydrolases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D055815:Young Adult
D002864:Chromogranins; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; C517834:PRKAR1A protein, human; D000324:Adrenocorticotropic Hormone; D000242:Cyclic AMP; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D017868:Cyclic AMP-Dependent Protein Kinases; D010727:Phosphoric Diester Hydrolases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; C468781:PDE8B protein, human; D015106:3',5'-Cyclic-GMP Phosphodiesterases; C406737:PDE11A protein, human; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs; D006854:Hydrocortisone