Phosphodiesterases (PDEs) regulate cyclic nucleotide levels. Increased cyclic AMP (cAMP) signaling has been associated with PRKAR1A or GNAS mutations and leads to adrenocortical tumors and Cushing syndrome1,2,3,4,5,6,7. We investigated the genetic source of Cushing syndrome in individuals with adrenocortical hyperplasia that was not caused by known defects. We performed genome-wide SNP genotyping, including the adrenocortical tumor DNA. The region with the highest probability to harbor a susceptibility gene by loss of heterozygosity (LOH) and other analyses was 2q31–2q35. We identified mutations disrupting the expression of the PDE11A isoform-4 gene (PDE11A) in three kindreds. Tumor tissues showed 2q31–2q35 LOH, decreased protein expression and high cyclic nucleotide levels and cAMP-responsive element binding protein (CREB) phosphorylation. PDE11A codes for a dual-specificity PDE that is expressed in adrenal cortex and is partially inhibited by tadalafil and other PDE inhibitors8,9; its germline inactivation is associated with adrenocortical hyperplasia, suggesting another means by which dysregulation of cAMP signaling causes endocrine tumors.
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This work is dedicated to our patients and their families. It was supported by US NIH intramural project Z01-HD-000642-04 to C.A.S. and, in part, by Groupement d'Intérêt Scientifique-Institut National de la Santé et de la Recherche Médicale Institut des Maladies Rares and the Plan Hospitalier de Recherche Clinique (AOM 02068) to the Comete Network. We thank S. Libutti and R. Alexander (National Cancer Institute (NCI), NIH) for expert surgical care on the individuals described in this study. We thank the nursing and other support staff of NICHD, NIH on the former 8W and 9W, and current 1NW and 5NW wards of the National Institutes of Health Warren Grant Magnuson Clinical Center for their support of our research studies and their help in the management of patients with adrenal tumors. We also thank D. Gunther (University of Washington, Seattle) and W.W. de Herder (Department of Internal Medicine, Endocrinology, Erasmus Medical Center, Rotterdam, the Netherlands) and the many other clinicians who have sent us samples from their patients. DNA samples from France were screened in that country for PRKAR1A mutations by E. Clauser, Unité d'Oncogénétique, CHU Cochin, Paris, and by E. Jullian, Institut Cochin, INSERM U567, Paris, to whom we are grateful. We thank C. Wayman (Discovery Biology, Pfizer Global Research and Development, Sandwich, Kent, UK) and J. Beavo (Department of Pharmacology, University of Washington, Seattle) for insightful advice in the field of PDE11A and their collaboration on the Pde11a−/− mouse. We thank I. Aksentijevich and E. Remmers (National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH), B. Brooks (National Eye Institute, NIH) and F. Porter (NICHD, NIH) for providing us with control DNA samples; K. Calis and F. Pucino (Pharmacy Department, NIH Clinical Center) for checking the PDE inhibitors toxicity database; and M. Abu-Asab and M. Tsokos (Laboratory of Pathology, NCI, NIH) for expert assistance with electron miscroscopy of adrenocortical specimens. We also thank V. Manganiello (National Heart, Lung and Blood Institute, NIH) and A. Spiegel (National Institute of Diabetes and Digestive and Kidney Diseases, NIH) for discussions on phosphodiesterases and cAMP signaling. We thank W.-Y. Chan's laboratory and staff (NICHD, NIH) for accommodating our increased sequencing needs and P. Soni for assisting with sequencing analysis. Finally, we thank C.A. Bondy and O.M. Rennert (NICHD, NIH) for editing our manuscript and for their continuing support of our studies.
De novo mutation and clinical data from family CAR36.
Expression of other PDEs in the adrenal cortex.
SNPs with significant LOH from chromosome 2q.
All sequence changes and number of controls.
Novel benign PDE11A4 polymorphisms.