title: 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.
abstract: Bilateral adrenocortical hyperplasia (BAH) is the second most common cause of corticotropin-independent Cushing syndrome (CS). Genetic forms of BAH have been associated with complex syndromes such as Carney Complex and McCune-Albright syndrome or may present as isolated micronodular adrenocortical disease (iMAD) usually in children and young adults with CS. A genome-wide association study identified inactivating phosphodiesterase (PDE) 11A (PDE11A)-sequencing defects as low-penetrance predisposing factors for iMAD and related abnormalities; we also described a mutation (c.914A > C/H305P) in cyclic AMP (cAMP)-specific PDE8B, in a patient with iMAD. In this study we further characterize this mutation; we also found a novel PDE8B isoform that is highly expressed in the adrenal gland. This mutation is shown to significantly affect the ability of the protein to degrade cAMP in vitro. Tumor tissues from patients with iMAD and no mutations in the coding PDE8B sequence or any other related genes (PRKAR1A, PDE11A) showed downregulated PDE8B expression (compared to normal adrenal cortex). Pde8b is detectable in the adrenal gland of newborn mice and is widely expressed in other mouse tissues. We conclude that PDE8B is another PDE gene linked to iMAD; it is a candidate causative gene for other adrenocortical lesions linked to the cAMP signaling pathway and possibly for tumors in other tissues.
authors.affiliation: Section on Endocrinology & Genetics, Program on Developmental Endocrinology & Genetics, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA. horvatha@mail.nih.gov
authors.forename: Anelia
authors.initials: A
authors.lastname: Horvath
authors.forename: Christoforos
authors.initials: C
authors.lastname: Giatzakis
authors.forename: Kitman
authors.initials: K
authors.lastname: Tsang
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Greene
authors.forename: Paulo
authors.initials: P
authors.lastname: Osorio
authors.forename: Sosipatros
authors.initials: S
authors.lastname: Boikos
authors.forename: Rossella
authors.initials: R
authors.lastname: Libè
authors.forename: Yianna
authors.initials: Y
authors.lastname: Patronas
authors.forename: Audrey
authors.initials: A
authors.lastname: Robinson-White
authors.forename: Elaine
authors.initials: E
authors.lastname: Remmers
authors.forename: Jerôme
authors.initials: J
authors.lastname: Bertherat
authors.forename: Maria
authors.initials: M
authors.lastname: Nesterova
authors.forename: Constantine A
authors.initials: CA
authors.lastname: Stratakis
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000737:chemistry / Q000235:genetics*; D000293:Adolescent; D000302:Adrenal Cortex / Q000201:enzymology*; D000303:Adrenal Cortex Diseases / Q000201:enzymology / Q000235:genetics; D000306:Adrenal Cortex Neoplasms / Q000201:enzymology / Q000235:genetics; D000312:Adrenal Hyperplasia, Congenital / Q000201:enzymology* / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D017124:Conserved Sequence; D003480:Cushing Syndrome / Q000201:enzymology / Q000235:genetics; D005260:Female; D006639:Histidine / Q000235:genetics; D006801:Humans; D007223:Infant; D007527:Isoenzymes / Q000737:chemistry / Q000235:genetics; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D011392:Proline / Q000235:genetics
chemical_list: D007527:Isoenzymes; D006639:Histidine; D011392:Proline; D015105:3',5'-Cyclic-AMP Phosphodiesterases; C468781:PDE8B protein, human