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Adrenal Hyperplasia and Adenomas Are Associated with Inhibition of Phosphodiesterase 11A in Carriers of PDE11A Sequence Variants That Are Frequent in the Population

¹ Section on Endocrinology and Genetics, Developmental Endocrinology Branch, National Institute of Child Health and Human Resources, NIH; ² Genetics and Genomics Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland; ³ Department of Internal Medicine, Endocrinology, Erasmus MC, Rotterdam, the Netherlands; ⁴ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota; ⁵ Institut National de la Sante et de la Recherche Medicale U567, Departement Endocrinologie, Metabolisme and Cancer, Institut Cochin, and Centre National de la Recherche Scientifique UMR 8104, and Centre de Reference des Maladies Rares de la Surrenale, Service d'Endocrinologie, Hôpital Cochin, Universite Paris 5, Paris, France and; ⁶ Feinstein Institute for Medical Research, North Shore LIJ Health System, Manhasset, New York

Requests for reprints: Constantine A. Stratakis, Section on Endocrinology and Genetics, Pediatric Endocrinology Training Program, DEB, National Institute of Child Health and Human Resources, NIH, Building 10, CRC, Room 1-3330, 10 Center Drive, MSC1103, Bethesda, MD 20892. Phone: 301-496-4686/496-6683; Fax: 301-402-0574/480-0378; E-mail: stratakc{at}mail.nih.gov.

Several types of adrenocortical tumors that lead to Cushing syndrome may be caused by aberrant cyclic AMP (cAMP) signaling. We recently identified patients with micronodular adrenocortical hyperplasia who were carriers of inactivating mutations in the 2q-located phosphodiesterase 11A (PDE11A) gene. We now studied the frequency of two missense substitutions, R804H and R867G, in conserved regions of the enzyme in several sets of normal controls, including 745 individuals enrolled in a longitudinal cohort study, the New York Cancer Project. In the latter, we also screened for the presence of the previously identified PDE11A nonsense mutations. R804H and R867G were frequent among patients with adrenocortical tumors; although statistical significance was not reached, these variants affected significantly enzymatic function in vitro with variable increases in cAMP and/or cyclic guanosine 3',5'-monophosphate levels in HeLa and HEK293 cells. Adrenocortical tissues carrying the R804H mutation showed 2q allelic losses and higher cyclic nucleotide levels and cAMP-responsive element binding protein phosphorylation. We conclude that missense mutations of the PDE11A gene that affect enzymatic activity in vitro are present in the general population; protein-truncating PDE11A mutations may also contribute to a predisposition to other tumors, in addition to their association with adrenocortical hyperplasia. We speculate that PDE11A genetic defects may be associated with adrenal pathology in a wider than previously suspected clinical spectrum that includes asymptomatic individuals. (Cancer Res 2006; 66(24): 11571-5)

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