Correspondence

Mutation in PDE8B, a Cyclic AMP–Specific Phosphodiesterase in Adrenal Hyperplasia

N Engl J Med 2008; 358:750-752February 14, 2008

Article

To the Editor:

Cortisol-producing adrenocortical tumors have been associated with abnormalities of the cyclic AMP (cAMP)–signaling pathway. Examples are Cushing's syndrome in infants with the McCune–Albright syndrome due to adrenocortical adenomas that harbor mutations of the stimulatory subunit alpha of G proteins (GNAS), primary pigmented nodular adrenocortical disease due to mutations of the protein kinase A regulatory subunit type 1A (PRKAR1A), and macronodular adrenocortical disease associated with aberrant expression of G-protein–coupled receptors in the tumor tissue.1,2 Recently, we performed a genomewide search for genes conferring a predisposition to micronodular adrenocortical hyperplasia, leading to Cushing's syndrome in childhood.3 We identified genetic loci harboring phosphodiesterase genes as those most likely to be linked to the disease, and inactivating mutations of phosphodiesterase 11A (the PDE11A gene) were associated with adrenocortical lesions, mostly micronodular hyperplasia.3,4 The chromosomal locus harboring the gene encoding phosphodiesterase 8B (PDE8B) was the second most likely region to be associated with a predisposition to micronodular adrenocortical hyperplasia.3 We also found significantly increased expression of PDE8B in the adrenal gland, as compared with other genes of phosphodiesterases that degrade cAMP, including PDE1A, PDE4A, PDE4B, PDE4C, PDE4D, PDE7A, and PDE9A.3

We sequenced the PDE8B coding regions in 20 patients with micronodular adrenocortical hyperplasia and identified a single base substitution (c.914A→C, p.His305Pro) in a young girl (Figure 1Figure 1Physical Evidence of Cushing's Syndrome in the Proband.) who had presented with Cushing's syndrome at the age of 2 years (Figure 2A and 2BFigure 2Imaging and Pathological Findings in the Proband.). The patient inherited the mutation from her father, who was not known to have Cushing's syndrome but was obese and had hypertension and abnormal midnight cortisol levels. Furthermore, the father had mild hyperplasia, especially of the left adrenal gland, shown on computed tomography. The c.914A→C substitution (Figure 2C) was not found in any of the 1030 unrelated control subjects studied. The His305Pro mutation affects an evolutionary conserved residue (Figure 2C). In vitro studies performed in HEK293 cells showed significantly higher cAMP levels after transfection with the mutant PDE8B than after transfection with the wild-type PDE8B (P=0.02), indicating an impaired ability of the mutant protein to degrade cAMP (Figure 2D).

PDE8B encodes the phosphodiesterase with the highest known affinity for cAMP.5 PDE8B-inactivating mutations appear to be a novel cause of an inherited predisposition to Cushing's syndrome in children. The involvement of PDE8B, along with that of PDE11A, GNAS, PRKAR1A, and the genes encoding the G-protein–coupled receptors that have been linked to food-dependent hypercortisolemia and other adrenocortical tumors, indicates the importance of abnormalities of the cAMP–signaling pathway in genetic causes of Cushing's syndrome.

Anelia Horvath, Ph.D.
National Institute of Child Health and Human Development, Bethesda, MD 20892

Veronica Mericq, M.D.
University of Chile, Santiago, Chile

Constantine A. Stratakis, M.D.
National Institute of Child Health and Human Development, Bethesda, MD 20892
stratakc@mail.nih.gov

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Citing Articles (20)

Citing Articles

1. 1

   Li-Chun Lisa Tsai, Joseph A Beavo. (2011) The roles of cyclic nucleotide phosphodiesterases (PDEs) in steroidogenesis. Current Opinion in Pharmacology 11:6, 670-675
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2. 2

   Isaac Levy, Anelia Horvath, Monalisa Azevedo, Rodrigo Bertollo de Alexandre, Constantine A Stratakis. (2011) Phosphodiesterase function and endocrine cells: links to human disease and roles in tumor development and treatment. Current Opinion in Pharmacology 11:6, 689-697
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3. 3

   D. Vezzosi, J. Bertherat. (2011) Phosphodiesterases in endocrine physiology and disease. European Journal of Endocrinology 165:2, 177-188
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4. 4

   Malgorzata Kumorowicz-Czoch, Katarzyna Dolezal-Oltarzewska, Dorota Roztoczynska, Malgorzata Chrupek, Andrzej Igor Prokurat, Grazyna Drabik, Jerzy Starzyk. (2011) Causes and consequences of abandoning one-stage bilateral adrenalectomy recommended in primary pigmented nodular adrenocortical disease – case presentation. Journal of Pediatric Endocrinology and Metabolism 24:7-8, 565-567
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5. 5

   Monalisa F. Azevedo, Constantine A. Stratakis. (2011) The Transcriptome that Mediates Increased Cyclic Adenosine Monophosphate Signaling in <i>PRKAR1A</i> Defects and Other Settings. Endocrine Practice 17:0, 2-7
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6. 6

   Madson Q. Almeida, Constantine A. Stratakis. (2011) How does cAMP/protein kinase A signaling lead to tumors in the adrenal cortex and other tissues?. Molecular and Cellular Endocrinology 336:1-2, 162-168
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   Madson Q. Almeida, Constantine A. Stratakis. (2010) Carney complex and other conditions associated with micronodular adrenal hyperplasias. Best Practice & Research Clinical Endocrinology & Metabolism 24:6, 907-914
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   Madson Q. Almeida, Constantine A. Stratakis. (2010) Solid tumors associated with multiple endocrine neoplasias. Cancer Genetics and Cytogenetics 203:1, 30-36
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   Harvinder S. Chahal, J. Paul Chapple, Lawrence A. Frohman, Ashley B. Grossman, Márta Korbonits. (2010) Clinical, genetic and molecular characterization of patients with familial isolated pituitary adenomas (FIPA). Trends in Endocrinology & Metabolism 21:7, 419-427
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    Charis Eng. (2010) Common alleles of predisposition in endocrine neoplasia. Current Opinion in Genetics & Development 20:3, 251-256
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    Georgette N. Jones, Parmeet K. Manchanda, Daphne R. Pringle, Mei Zhang, Lawrence S. Kirschner. (2010) Mouse models of endocrine tumours. Best Practice & Research Clinical Endocrinology & Metabolism 24:3, 451-460
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12. 12

    J. Aidan Carney, Rolf C. Gaillard, Jérôme Bertherat, Constantine A. Stratakis. (2010) Familial Micronodular Adrenocortical Disease, Cushing Syndrome, and Mutations of the Gene Encoding Phosphodiesterase 11A4 (PDE11A). The American Journal of Surgical Pathology 34:4, 547-555
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13. 13

    Anelia Horvath, Fabio Faucz, Gabriela P. Finkielstain, Maria Eleni Nikita, Anya Rothenbuhler, Madson Almeida, Veronica Mericq, Constantine A. Stratakis. (2010) Haplotype Analysis of the Promoter Region of Phosphodiesterase Type 8B ( PDE8B ) in Correlation with Inactivating PDE8B Mutation and the Serum Thyroid-Stimulating Hormone Levels. Thyroid 20:4, 363-367
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14. 14

    Anelia Horvath, Constantine A. Stratakis. (2009) Carney complex and lentiginosis. Pigment Cell & Melanoma Research 22:5, 580-587
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    M. Alevizaki, C. A. Stratakis. (2009) Multiple endocrine neoplasias: advances and challenges for the future. Journal of Internal Medicine 266:1, 1-4
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16. 16

    L. S. Kirschner. (2009) Use of mouse models to understand the molecular basis of tissue-specific tumorigenesis in the Carney complex. Journal of Internal Medicine 266:1, 60-68
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17. 17

    Constantine A. Stratakis. (2009) New genes and/or molecular pathways associated with adrenal hyperplasias and related adrenocortical tumors. Molecular and Cellular Endocrinology 300:1-2, 152-157
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18. 18

    Anelia Horvath, Christoforos Giatzakis, Kitman Tsang, Elizabeth Greene, Paulo Osorio, Sosipatros Boikos, Rossella Libè, Yianna Patronas, Audrey Robinson-White, Elaine Remmers, Jerôme Bertherat, Maria Nesterova, Constantine A Stratakis. (2008) A cAMP-specific phosphodiesterase (PDE8B) that is mutated in adrenal hyperplasia is expressed widely in human and mouse tissues: a novel PDE8B isoform in human adrenal cortex. European Journal of Human Genetics 16:10, 1245-1253
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    Lisette Arnaud-Lopez, Gianluca Usala, Graziano Ceresini, Braxton D. Mitchell, Maria Grazia Pilia, Maria Grazia Piras, Natascia Sestu, Andrea Maschio, Fabio Busonero, Giuseppe Albai, Mariano Dei, Sandra Lai, Antonella Mulas, Laura Crisponi, Toshiko Tanaka, Stefania Bandinelli, Jack M. Guralnik, Angela Loi, Lenuta Balaci, Gabriella Sole, Alessia Prinzis, Stefano Mariotti, Alan R. Shuldiner, Antonio Cao, David Schlessinger, Manuela Uda, Gonçalo R. Abecasis, Ramaiah Nagaraja, Serena Sanna, Silvia Naitza. (2008) Phosphodiesterase 8B Gene Variants Are Associated with Serum TSH Levels and Thyroid Function. The American Journal of Human Genetics 82:6, 1270-1280
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20. 20

    Anelia Horvath, Constantine A Stratakis. (2008) Unraveling the molecular basis of micronodular adrenal hyperplasia. Current Opinion in Endocrinology, Diabetes and Obesity 15:3, 227-233
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