title: 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.affiliation: Section on Endocrinology & Genetics, Developmental Endocrinology Branch, US National Institute of Child Health and Human Development, US National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Anelia
authors.initials: A
authors.lastname: Horvath
authors.forename: Sosipatros
authors.initials: S
authors.lastname: Boikos
authors.forename: Christoforos
authors.initials: C
authors.lastname: Giatzakis
authors.forename: Audrey
authors.initials: A
authors.lastname: Robinson-White
authors.forename: Lionel
authors.initials: L
authors.lastname: Groussin
authors.forename: Kurt J
authors.initials: KJ
authors.lastname: Griffin
authors.forename: Erica
authors.initials: E
authors.lastname: Stein
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Levine
authors.forename: Georgia
authors.initials: G
authors.lastname: Delimpasi
authors.forename: Hui Pin
authors.initials: HP
authors.lastname: Hsiao
authors.forename: Meg
authors.initials: M
authors.lastname: Keil
authors.forename: Sarah
authors.initials: S
authors.lastname: Heyerdahl
authors.forename: Ludmila
authors.initials: L
authors.lastname: Matyakhina
authors.forename: Rossella
authors.initials: R
authors.lastname: Libè
authors.forename: Amato
authors.initials: A
authors.lastname: Fratticci
authors.forename: Lawrence S
authors.initials: LS
authors.lastname: Kirschner
authors.forename: Kevin
authors.initials: K
authors.lastname: Cramer
authors.forename: Rolf C
authors.initials: RC
authors.lastname: Gaillard
authors.forename: Xavier
authors.initials: X
authors.lastname: Bertagna
authors.forename: J Aidan
authors.initials: JA
authors.lastname: Carney
authors.forename: Jérôme
authors.initials: J
authors.lastname: Bertherat
authors.forename: Ioannis
authors.initials: I
authors.lastname: Bossis
authors.forename: Constantine A
authors.initials: CA
authors.lastname: Stratakis
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000311:Adrenal Glands / Q000201:enzymology* / Q000473:pathology*; D000328:Adult; D002648:Child; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D003480:Cushing Syndrome / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D005260:Female; D006801:Humans; D006965:Hyperplasia; D019656:Loss of Heterozygosity; D008297:Male; D009154:Mutation; D010727:Phosphoric Diester Hydrolases / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide
chemical_list: D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; C406737:PDE11A protein, human