PDE11A (phosphodiesterase 11A)
2010-01-01 Rossella Libé , Jérôme Bertherat AffiliationINSERM U567, CNRS 8104, Institut Cochin, Service de Maladies Endocriniennes et Metabolique, Hopital Cochin, Paris, France
Identity
HGNC
LOCATION
2q31.2
IMAGE
LOCUSID
ALIAS
PPNAD2
FUSION GENES
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.
Proteins
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.
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%.
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.
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
Entity name
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 name
ACTH-independent macronodular adrenal hyperplasia (AIMAH)
Disease
AIMAH is a rare form of benign bilateral adrenocortical tumor. It can be associated to an overt Cushings 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 name
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 name
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.
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 15627479 | 2005 | Dexamethasone down-regulates cAMP-phosphodiesterase in human osteosarcoma cells. | Ahlström M et al |
| 19522821 | 2009 | Multiple endocrine neoplasias: advances and challenges for the future. | Alevizaki M et al |
| 19429701 | 2009 | Abnormalities of cAMP signaling are present in adrenocortical lesions associated with ACTH-independent Cushing syndrome despite the absence of mutations in known genes. | Bimpaki EI et al |
| 18491255 | 2008 | Phosphodiesterase 11A expression in the adrenal cortex, primary pigmented nodular adrenocortical disease, and other corticotropin-independent lesions. | Boikos SA et al |
| 19214142 | 2009 | Association study of phosphodiesterase genes in the Sequenced Treatment Alternatives to Relieve Depression sample. | Cabanero M et al |
| 17036196 | 2006 | PRKAR1A mutations in primary pigmented nodular adrenocortical disease. | Cazabat L et al |
| 15995148 | 2005 | Expression of PDE11A in normal and malignant human tissues. | D'Andrea MR et al |
| 10725373 | 2000 | Molecular cloning and characterization of a distinct human phosphodiesterase gene family: PDE11A. | Fawcett L et al |
| 16079899 | 2005 | Phosphodiesterase 11 (PDE11): is it a player in human testicular function? | Francis SH et al |
| 18312413 | 2008 | The properties of phosphodiesterase 11A4 GAF domains are regulated by modifications in its N-terminal domain. | Gross-Langenhoff M et al |
| 11050148 | 2000 | Cloning and characterization of two splice variants of human phosphodiesterase 11A. | Hetman JM et al |
| 16767104 | 2006 | A genome-wide scan identifies mutations in the gene encoding phosphodiesterase 11A4 (PDE11A) in individuals with adrenocortical hyperplasia. | Horvath A et al |
| 18431404 | 2008 | A cAMP-specific phosphodiesterase (PDE8B) that is mutated in adrenal hyperplasia is expressed widely in human and mouse tissues: a novel PDE8B isoform in human adrenal cortex. | Horvath A et al |
| 19549888 | 2009 | Functional phosphodiesterase 11A mutations may modify the risk of familial and bilateral testicular germ cell tumors. | Horvath A et al |
| 18438169 | 2008 | Unraveling the molecular basis of micronodular adrenal hyperplasia. | Horvath A et al |
| 19509103 | 2009 | Clinical and genetic heterogeneity, overlap with other tumor syndromes, and atypical glucocorticoid hormone secretion in adrenocorticotropin-independent macronodular adrenal hyperplasia compared with other adrenocortical tumors. | Hsiao HP et al |
| 19445908 | 2009 | PDE9A, PDE10A, and PDE11A expression in rat trigeminovascular pain signalling system. | Kruse LS et al |
| 19880459 | 2009 | Pharmacogenetics studies in STAR*D: strengths, limitations, and results. | Laje G et al |
| 18559625 | 2008 | Phosphodiesterase 11A (PDE11A) and genetic predisposition to adrenocortical tumors. | Libé R et al |
| 15800651 | 2005 | 3',5'-cyclic nucleotide phosphodiesterase 11A: localization in human tissues. | Loughney K et al |
| 19915020 | 2010 | ACTH-independent Cushing's syndrome with bilateral micronodular adrenal hyperplasia and ectopic adrenocortical adenoma. | Louiset E et al |
| 19557111 | 2009 | Association of PDE11A global haplotype with major depression and antidepressant drug response. | Luo HR et al |
| 19689430 | 2009 | Binding of cyclic nucleotides to phosphodiesterase 10A and 11A GAF domains does not stimulate catalytic activity. | Matthiesen K et al |
| 19540112 | 2009 | Identification, synthesis and SAR of amino substituted pyrido[3,2b]pyrazinones as potent and selective PDE5 inhibitors. | Owen DR et al |
| 19671705 | 2009 | Analysis of genetic variants of phosphodiesterase 11A in acromegalic patients. | Peverelli E et al |
| 17544419 | 2007 | Alterations in sperm motility after acute oral administration of sildenafil or tadalafil in young, infertile men. | Pomara G et al |
| 16094044 | 2005 | Phosphodiesterase 11 (PDE11) regulation of spermatozoa physiology. | Seftel AD et al |
| 19063937 | 2009 | New genes and/or molecular pathways associated with adrenal hyperplasias and related adrenocortical tumors. | Stratakis CA et al |
| 18419788 | 2008 | Detection of somatic beta-catenin mutations in primary pigmented nodular adrenocortical disease (PPNAD). | Tadjine M et al |
| 18043711 | 2007 | Variants in PDE11A and PDE1A are not associated with citalopram response. | Teranishi KS et al |
| 19068395 | 2008 | [Sporadic adrenocortical tumors: genetics and perspectives for the pathologist]. | Tissier F et al |
| 18706893 | 2008 | Phosphodiesterase 3 and 4 comprise the major cAMP metabolizing enzymes responsible for insulin secretion in INS-1 (832/13) cells and rat islets. | Waddleton D et al |
| 15800654 | 2005 | Phosphodiesterase 11 (PDE11) regulation of spermatozoa physiology. | Wayman C et al |
| 19641165 | 2009 | Interactions between cyclic nucleotide phosphodiesterase 11 catalytic site and substrates or tadalafil and role of a critical Gln-869 hydrogen bond. | Weeks JL 2nd et al |
| 15538396 | 2005 | High biochemical selectivity of tadalafil, sildenafil and vardenafil for human phosphodiesterase 5A1 (PDE5) over PDE11A4 suggests the absence of PDE11A4 cross-reaction in patients. | Weeks JL et al |
| 17008408 | 2006 | Phosphodiesterase genes are associated with susceptibility to major depression and antidepressant treatment response. | Wong ML et al |
| 11121118 | 2001 | Genomic organization of the human phosphodiesterase PDE11A gene. Evolutionary relatedness with other PDEs containing GAF domains. | Yuasa K et al |
| 10906126 | 2000 | Isolation and characterization of two novel phosphodiesterase PDE11A variants showing unique structure and tissue-specific expression. | Yuasa K et al |
| 11502204 | 2001 | Identification of rat cyclic nucleotide phosphodiesterase 11A (PDE11A): comparison of rat and human PDE11A splicing variants. | Yuasa K et al |
| 11134002 | 2001 | Characterization of TbPDE2A, a novel cyclic nucleotide-specific phosphodiesterase from the protozoan parasite Trypanosoma brucei. | Zoraghi R et al |
Other Information
Locus ID:
NCBI: 50940
MIM: 604961
HGNC: 8773
Ensembl: ENSG00000284741
Variants:
dbSNP: 50940
ClinVar: 50940
TCGA: ENSG00000284741
COSMIC: PDE11A
RNA/Proteins
Pathways
Protein levels (Protein atlas)
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 33661511 | 2021 | PDE11A gene polymorphism in testicular cancer: sperm parameters and hormonal profile. | 4 |
| 33835157 | 2021 | Exome sequencing revealed PDE11A as a novel candidate gene for early-onset Alzheimer's disease. | 6 |
| 33661511 | 2021 | PDE11A gene polymorphism in testicular cancer: sperm parameters and hormonal profile. | 4 |
| 33835157 | 2021 | Exome sequencing revealed PDE11A as a novel candidate gene for early-onset Alzheimer's disease. | 6 |
| 26820475 | 2016 | A stop-codon of the phosphodiesterase 11A gene is associated with elevated blood pressure and measures of obesity. | 7 |
| 26820475 | 2016 | A stop-codon of the phosphodiesterase 11A gene is associated with elevated blood pressure and measures of obesity. | 7 |
| 26459559 | 2015 | Rare inactivating PDE11A variants associated with testicular germ cell tumors. | 13 |
| 26459559 | 2015 | Rare inactivating PDE11A variants associated with testicular germ cell tumors. | 13 |
| 22996146 | 2012 | Phosphodiesterase 11A (PDE11A) gene defects in patients with acth-independent macronodular adrenal hyperplasia (AIMAH): functional variants may contribute to genetic susceptibility of bilateral adrenal tumors. | 35 |
| 22996146 | 2012 | Phosphodiesterase 11A (PDE11A) gene defects in patients with acth-independent macronodular adrenal hyperplasia (AIMAH): functional variants may contribute to genetic susceptibility of bilateral adrenal tumors. | 35 |
| 20351714 | 2011 | Poor replication of candidate genes for major depressive disorder using genome-wide association data. | 119 |
| 20881257 | 2011 | Phosphodiesterase 11A (PDE11A) genetic variants may increase susceptibility to prostatic cancer. | 27 |
| 20881257 | 2011 | Phosphodiesterase 11A (PDE11A) genetic variants may increase susceptibility to prostatic cancer. | 27 |
| 21047926 | 2011 | Frequent phosphodiesterase 11A gene (PDE11A) defects in patients with Carney complex (CNC) caused by PRKAR1A mutations: PDE11A may contribute to adrenal and testicular tumors in CNC as a modifier of the phenotype. | 43 |
| 21047926 | 2011 | Frequent phosphodiesterase 11A gene (PDE11A) defects in patients with Carney complex (CNC) caused by PRKAR1A mutations: PDE11A may contribute to adrenal and testicular tumors in CNC as a modifier of the phenotype. | 43 |
Citation
Rossella Libé ; Jérôme Bertherat
PDE11A (phosphodiesterase 11A)
Atlas Genet Cytogenet Oncol Haematol. 2010-01-01
Online version: http://atlasgeneticsoncology.org/gene/44448/pde11a-(phosphodiesterase-11a)
