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

Details

Serval ID
serval:BIB_308E0F784C0F
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
A genome-wide scan identifies mutations in the gene encoding phosphodiesterase 11A4 (PDE11A) in individuals with adrenocortical hyperplasia
Journal
Nature Genetics
Author(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)
Publication state
Published
Issued date
07/2006
Volume
38
Number
7
Pages
794-800
Notes
Journal Article
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't --- Old month value: Jul
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.
Keywords
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
Create date
15/02/2008 16:57
Last modification date
20/08/2019 13:15
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