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

Détails

ID Serval
serval:BIB_308E0F784C0F
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
A genome-wide scan identifies mutations in the gene encoding phosphodiesterase 11A4 (PDE11A) in individuals with adrenocortical hyperplasia
Périodique
Nature Genetics
Auteur(s)
Horvath  A., Boikos  S., Giatzakis  C., Robinson-White  A., Groussin  L., Griffin  K. J., Stein  E., Levine  E., Delimpasi  G., Hsiao  H. P., Keil  M., Heyerdahl  S., Matyakhina  L., Libe  R., Fratticci  A., Kirschner  L. S., Cramer  K., Gaillard  R. C., Bertagna  X., Carney  J. A., Bertherat  J., Bossis  I., Stratakis  C. A.
ISSN
1061-4036 (Print)
Statut éditorial
Publié
Date de publication
07/2006
Volume
38
Numéro
7
Pages
794-800
Notes
Journal Article
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't --- Old month value: Jul
Résumé
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.
Mots-clé
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
Pubmed
Web of science
Création de la notice
15/02/2008 17:57
Dernière modification de la notice
20/08/2019 14:15
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