A genome-wide scan identifies mutations in the gene encoding phosphodiesterase 11A4 (PDE11A) in individuals with adrenocortical hyperplasia.
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.
Horvath
Anelia
A
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.
Boikos
Sosipatros
S
Giatzakis
Christoforos
C
Robinson-White
Audrey
A
Groussin
Lionel
L
Griffin
Kurt J
KJ
Stein
Erica
E
Levine
Elizabeth
E
Delimpasi
Georgia
G
Hsiao
Hui Pin
HP
Keil
Meg
M
Heyerdahl
Sarah
S
Matyakhina
Ludmila
L
Libè
Rossella
R
Fratticci
Amato
A
Kirschner
Lawrence S
LS
Cramer
Kevin
K
Gaillard
Rolf C
RC
Bertagna
Xavier
X
Carney
J Aidan
JA
Bertherat
Jérôme
J
Bossis
Ioannis
I
Stratakis
Constantine A
CA
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
D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; C406737:PDE11A protein, human