title: Adrenal hyperplasia and adenomas are associated with inhibition of phosphodiesterase 11A in carriers of PDE11A sequence variants that are frequent in the population.
abstract: Several types of adrenocortical tumors that lead to Cushing syndrome may be caused by aberrant cyclic AMP (cAMP) signaling. We recently identified patients with micronodular adrenocortical hyperplasia who were carriers of inactivating mutations in the 2q-located phosphodiesterase 11A (PDE11A) gene. We now studied the frequency of two missense substitutions, R804H and R867G, in conserved regions of the enzyme in several sets of normal controls, including 745 individuals enrolled in a longitudinal cohort study, the New York Cancer Project. In the latter, we also screened for the presence of the previously identified PDE11A nonsense mutations. R804H and R867G were frequent among patients with adrenocortical tumors; although statistical significance was not reached, these variants affected significantly enzymatic function in vitro with variable increases in cAMP and/or cyclic guanosine 3',5'-monophosphate levels in HeLa and HEK293 cells. Adrenocortical tissues carrying the R804H mutation showed 2q allelic losses and higher cyclic nucleotide levels and cAMP-responsive element binding protein phosphorylation. We conclude that missense mutations of the PDE11A gene that affect enzymatic activity in vitro are present in the general population; protein-truncating PDE11A mutations may also contribute to a predisposition to other tumors, in addition to their association with adrenocortical hyperplasia. We speculate that PDE11A genetic defects may be associated with adrenal pathology in a wider than previously suspected clinical spectrum that includes asymptomatic individuals.
authors.affiliation: Section on Endocrinology and Genetics, Developmental Endocrinology Branch, National Institute of Child Health and Human Resources, NIH, Bethesda, MD 20892, USA.
authors.forename: Anelia
authors.initials: A
authors.lastname: Horvath
authors.forename: Christoforos
authors.initials: C
authors.lastname: Giatzakis
authors.forename: Audrey
authors.initials: A
authors.lastname: Robinson-White
authors.forename: Sosipatros
authors.initials: S
authors.lastname: Boikos
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Levine
authors.forename: Kurt
authors.initials: K
authors.lastname: Griffin
authors.forename: Erica
authors.initials: E
authors.lastname: Stein
authors.forename: Virginia
authors.initials: V
authors.lastname: Kamvissi
authors.forename: Payal
authors.initials: P
authors.lastname: Soni
authors.forename: Ioannis
authors.initials: I
authors.lastname: Bossis
authors.forename: Wouter
authors.initials: W
authors.lastname: de Herder
authors.forename: J Aidan
authors.initials: JA
authors.lastname: Carney
authors.forename: Jérôme
authors.initials: J
authors.lastname: Bertherat
authors.forename: Peter K
authors.initials: PK
authors.lastname: Gregersen
authors.forename: Elaine F
authors.initials: EF
authors.lastname: Remmers
authors.forename: Constantine A
authors.initials: CA
authors.lastname: Stratakis
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000236:Adenoma / Q000201:enzymology / Q000235:genetics*; D000308:Adrenocortical Hyperfunction / Q000201:enzymology* / Q000235:genetics*; D001483:Base Sequence; D002353:Carrier State; D002460:Cell Line; D018389:Codon, Nonsense; D003480:Cushing Syndrome / Q000201:enzymology / Q000235:genetics; D004247:DNA / Q000235:genetics; D017931:DNA Primers; D004273:DNA, Neoplasm / Q000235:genetics; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D006367:HeLa Cells; D006801:Humans; D007668:Kidney; D019656:Loss of Heterozygosity; D009154:Mutation; D010727:Phosphoric Diester Hydrolases / Q000235:genetics*; D010911:Pituitary Neoplasms / Q000201:enzymology / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; D017931:DNA Primers; D004273:DNA, Neoplasm; D004247:DNA; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; C406737:PDE11A protein, human