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PDE11A (phosphodiesterase 11A)

Written2010-01Rossella Libé, Jérôme Bertherat
INSERM U567, CNRS 8104, Institut Cochin, Service de Maladies Endocriniennes et Metabolique, Hopital Cochin, Paris, France

(Note : for Links provided by Atlas : click)

Identity

Other aliasFLJ23693
MGC133355
MGC133356
PDE11A1
PDE11A2
PDE11A3
PPNAD2
LocusID (NCBI) 50940
Atlas_Id 44448
Location 2q31.2  [Link to chromosome band 2q31]
Location_base_pair Starts at and ends at bp from pter
 
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
ITGAV (2q32.1) / PDE11A (2q31.2)NFE2L2 (2q31.2) / PDE11A (2q31.2)

DNA/RNA

 
Description PDE11A is the most recently discovered PDE enzyme family. In this family, only one gene, PDE11A, has been identified. It is a dual phosphodiesterase that hydrolyzes both cAMP and cGMP.
Transcription Four different isoforms of PDE11A (PDE11A1→A4) have been identified. The longest variant, PDE11A4 is composed of 20 coding exons of varying length, separated by introns, giving the gene a total length of 4441 bps.

Protein

Description PDE11A4 is a protein of 104 kDa: it contains two N-terminal GAF domains (between exons 3-12) and one C-terminal catalytic domain (between exons 14-22).
Expression Isoform 1 is present in prostate, pituitary, heart, liver and skeletal muscle. Isoform 2 and 3 are expressed in the testis. Isoform 4 is the only isoform of the enzyme expressed in the adrenal cortex, where it is expressed substantially less than in the prostate.
Localisation Cytoplasm > cytosol.
Function PDE11A enzymes catalyze the hydrolysis of both cAMP and cGMP to 5'-AMP and 5'-GMP, respectively. This takes part in the down-regulation of the cAMP and cGMP signaling.
Inactive mutations of the isoform PDE11A4 gene have been identified in patients with adrenal Cushing syndrome due to micronodular adrenocortical hyperplasia. An association of PDE11A4 variants and other neoplasms is suggested since a higher frequency of PDE11A4 missense mutations is observed in patients with macronodular adrenal hyperplasia and testicular tumors than in the controls.
Homology The catalytic domain is conserved among the 4 isoforms of PDE11A.
A high sequence similarity of 42-51% is found within the amino acid sequences of the catalytic regions of PDEs containing a Gaf sequence (i.e. PDE2A, PDE5A, PDE6B, PDE6C, PDE10A and PDE11A).
Gene conserved among species: Pan troglodytes: 98.6%; Canis lupus familiaris: 96.4%; Bos taurus: 95.9%; Mus musculus: 94.6%; Rattus norvegicus: 94.5%; Gallus gallus: 90%; Danio rerio: 90%.

Mutations

 
  Non-sense mutations (yellow) and missense mutations (green) described in adrenocortical tumor (PPNAD, AIMAH, ACA and ACC).
Germinal Non sense.
Three PDE11A nonsense mutations leading to a premature stop codon were identified in 3 kindreds with adrenal Cushing syndrome due to micronodular adrenocortical hyperplasia.
Other missense mutations (genetic variants) are described in adrenocortical tumor, as macronodular adrenal hyperplasia (AIMAH), adrenocortical adenoma (ACA), adrenocortical carcinoma (ACC) and testicular tumors.
Somatic Loss of heterozygosity with loss of wild type allele have been reported in adrenocortical tumor (benign and malignant) with PDE11A4 missense mutations.

Implicated in

Note
  
Entity Adrenal Cushing syndrome due to micronodular adrenocortical hyperplasia
Disease ACTH-independant chronic oversecretion of cortisol due to bilateral adrenal involvement. Pathological examination demonstrates diffuse micronodular hyperaplasia of the cortex of both adrenal. These nodules can be pigmented as observed in primary pigmented nodular adrenocortical disease (PPNAD).
Prognosis Morbidity and mortality of non treated Cushing syndrome is high. However after treatment (bilateral adrenalectomy in most cases) there is a clear improvement and the overall prognosis is good, the main side effect of the treatment being adrenal deficiency.
Oncogenesis In the patients with non-sense mutations a loss of the wild type allele was demonstrated in the adrenal nodes, supporting the hypothesis that PDE11A4 is a tumor suppressor gene.
  
  
Entity ACTH-independent macronodular adrenal hyperplasia (AIMAH)
Disease AIMAH is a rare form of benign bilateral adrenocortical tumor. It can be associated to an overt Cushing's syndrome (CS). Nowadays, the most frequent clinical presentation is that of bilateral adrenal incidentalomas. The initial endocrine evaluation usually demonstrates subtle abnormalities of cortisol secretion, suggesting a subclinical CS.
Prognosis Morbidity and mortality of non treated Cushing syndrome is high. However after treatment (bilateral adrenalectomy in most cases) there is a clear improvement and the overall prognosis is good, the main side effect of the treatment being adrenal deficiency.
Cytogenetics A higher frequency of missense PDE11A mutations (genetic variants) than in healthy subjects are found.
Oncogenesis The higher frequency of PDE11A missense mutations suggests a role of PDE11A in the genetic predisposition to adrenal tumors.
  
  
Entity Testicular germ cells tumors (TGCT)
Disease It is the most common malignancy in Caucasian men aged from 15 to 45 years old. A genetic basis for TGCT is supported by familial clustering, younger-than-usual age at diagnosis, and an increased risk of bilateral disease.
Prognosis More than 90% of patients with newly diagnosed TGCT are cured, and delay in diagnosis correlates with a higher stage at presentation for treatment.
Cytogenetics Recently, PDE11A missense mutations (genetic variants) have been reported in TGCT. The frequency was significantly higher in patients with TGCT than in healthy subjects.
Oncogenesis PDE11A variants are involved in the testicular tumorigenesis and may modify the risk of familial and bilateral TGCT.
  
  
Entity Adrenocortical carcinoma (ACC)
Disease ACC is a rare malignant tumor, with an estimated prevalence between 4 and 12 per million in adults.
Prognosis The overall survival varies according to tumor stage. However the overall survival is poor and below 30% at 5 years in most series.
Cytogenetics A higher frequency of a polymorphism in exon 6 (E421E) and of three associated polymorphisms located in intron 10-exon 11-intron 11 is found in ACCs than in healthy subjects.
Oncogenesis The synonymous E421E variant and the intron 10/intron 11 variants could play a role in the predisposition to ACC development.
  

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Citation

This paper should be referenced as such :
Libé, R ; Bertherat, J
PDE11A (phosphodiesterase 11A)
Atlas Genet Cytogenet Oncol Haematol. 2010;14(11):1027-1031.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/PDE11AID44448ch2q31.html


Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 2 ]
  NFE2L2/PDE11A (2q31)
t(2;2)(q31;q32) ITGAV/PDE11A


External links

Nomenclature
Cards
AtlasPDE11AID44448ch2q31.txt
Aliases
Genomic and cartography
Gene and transcription
RefSeq transcript (Entrez)
RefSeq genomic (Entrez)
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
BioGPS (Tissue expression)50940
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Protein Interaction databases
Ontologies - Pathways
Clinical trials, drugs, therapy
Miscellaneous
canSAR (ICR) (select the gene name)
Probes
Litterature
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed


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