A genome-wide scan identifies mutations in the gene encoding phosphodiesterase 11A4 (PDE11A) in individuals with adrenocortical hyperplasia.

Abstract

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 syndrome. 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 inhibitors; its germline inactivation is associated with adrenocortical hyperplasia, suggesting another means by which dysregulation of cAMP signaling causes endocrine tumors.

• Authors: Anelia Horvath, Sosipatros Boikos, Christoforos Giatzakis, Audrey Robinson-White, Lionel Groussin, Kurt J Griffin, Erica Stein, Elizabeth Levine, Georgia Delimpasi, Hui Pin Hsiao, Meg Keil, Sarah Heyerdahl, Ludmila Matyakhina, Rossella Libè, Amato Fratticci, Lawrence S Kirschner, Kevin Cramer, Rolf C Gaillard, Xavier Bertagna, J Aidan Carney, Jérôme Bertherat, Ioannis Bossis, Constantine A Stratakis
• Journal: Nature genetics (Nat Genet) Vol. 38 Issue 7 Pg. 794-800 (Jul 2006) ISSN: 1061-4036 [Print] United States
• PMID: 16767104 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Phosphoric Diester Hydrolases
• 3',5'-Cyclic-GMP Phosphodiesterases
• PDE11A protein, human

Topics

• 3',5'-Cyclic-GMP Phosphodiesterases
• Adrenal Glands (enzymology, pathology)
• Adult
• Child
• Chromosomes, Human, Pair 2 (genetics)
• Cushing Syndrome (enzymology, genetics, pathology)
• Female
• Humans
• Hyperplasia
• Loss of Heterozygosity
• Male
• Mutation
• Phosphoric Diester Hydrolases (genetics, metabolism)
• Polymorphism, Single Nucleotide