PDE11A (phosphodiesterase 11A)

2010-01-01   Rossella Libé , Jérôme Bertherat 

INSERM U567, CNRS 8104, Institut Cochin, Service de Maladies Endocriniennes et Metabolique, Hopital Cochin, Paris, France

Identity

HGNC
LOCATION
2q31.2
IMAGE
Atlas Image
LOCUSID
ALIAS
PPNAD2
FUSION GENES

DNA/RNA

Atlas Image

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.

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

Atlas Image
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

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.

Bibliography

Pubmed IDLast YearTitleAuthors
156274792005Dexamethasone down-regulates cAMP-phosphodiesterase in human osteosarcoma cells.Ahlström M et al
195228212009Multiple endocrine neoplasias: advances and challenges for the future.Alevizaki M et al
194297012009Abnormalities 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
184912552008Phosphodiesterase 11A expression in the adrenal cortex, primary pigmented nodular adrenocortical disease, and other corticotropin-independent lesions.Boikos SA et al
192141422009Association study of phosphodiesterase genes in the Sequenced Treatment Alternatives to Relieve Depression sample.Cabanero M et al
170361962006PRKAR1A mutations in primary pigmented nodular adrenocortical disease.Cazabat L et al
159951482005Expression of PDE11A in normal and malignant human tissues.D'Andrea MR et al
107253732000Molecular cloning and characterization of a distinct human phosphodiesterase gene family: PDE11A.Fawcett L et al
160798992005Phosphodiesterase 11 (PDE11): is it a player in human testicular function?Francis SH et al
183124132008The properties of phosphodiesterase 11A4 GAF domains are regulated by modifications in its N-terminal domain.Gross-Langenhoff M et al
110501482000Cloning and characterization of two splice variants of human phosphodiesterase 11A.Hetman JM et al
167671042006A genome-wide scan identifies mutations in the gene encoding phosphodiesterase 11A4 (PDE11A) in individuals with adrenocortical hyperplasia.Horvath A et al
184314042008A 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
195498882009Functional phosphodiesterase 11A mutations may modify the risk of familial and bilateral testicular germ cell tumors.Horvath A et al
184381692008Unraveling the molecular basis of micronodular adrenal hyperplasia.Horvath A et al
195091032009Clinical 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
194459082009PDE9A, PDE10A, and PDE11A expression in rat trigeminovascular pain signalling system.Kruse LS et al
198804592009Pharmacogenetics studies in STAR*D: strengths, limitations, and results.Laje G et al
185596252008Phosphodiesterase 11A (PDE11A) and genetic predisposition to adrenocortical tumors.Libé R et al
1580065120053',5'-cyclic nucleotide phosphodiesterase 11A: localization in human tissues.Loughney K et al
199150202010ACTH-independent Cushing's syndrome with bilateral micronodular adrenal hyperplasia and ectopic adrenocortical adenoma.Louiset E et al
195571112009Association of PDE11A global haplotype with major depression and antidepressant drug response.Luo HR et al
196894302009Binding of cyclic nucleotides to phosphodiesterase 10A and 11A GAF domains does not stimulate catalytic activity.Matthiesen K et al
195401122009Identification, synthesis and SAR of amino substituted pyrido[3,2b]pyrazinones as potent and selective PDE5 inhibitors.Owen DR et al
196717052009Analysis of genetic variants of phosphodiesterase 11A in acromegalic patients.Peverelli E et al
175444192007Alterations in sperm motility after acute oral administration of sildenafil or tadalafil in young, infertile men.Pomara G et al
160940442005Phosphodiesterase 11 (PDE11) regulation of spermatozoa physiology.Seftel AD et al
190639372009New genes and/or molecular pathways associated with adrenal hyperplasias and related adrenocortical tumors.Stratakis CA et al
184197882008Detection of somatic beta-catenin mutations in primary pigmented nodular adrenocortical disease (PPNAD).Tadjine M et al
180437112007Variants in PDE11A and PDE1A are not associated with citalopram response.Teranishi KS et al
190683952008[Sporadic adrenocortical tumors: genetics and perspectives for the pathologist].Tissier F et al
187068932008Phosphodiesterase 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
158006542005Phosphodiesterase 11 (PDE11) regulation of spermatozoa physiology.Wayman C et al
196411652009Interactions 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
155383962005High 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
170084082006Phosphodiesterase genes are associated with susceptibility to major depression and antidepressant treatment response.Wong ML et al
111211182001Genomic organization of the human phosphodiesterase PDE11A gene. Evolutionary relatedness with other PDEs containing GAF domains.Yuasa K et al
109061262000Isolation and characterization of two novel phosphodiesterase PDE11A variants showing unique structure and tissue-specific expression.Yuasa K et al
115022042001Identification of rat cyclic nucleotide phosphodiesterase 11A (PDE11A): comparison of rat and human PDE11A splicing variants.Yuasa K et al
111340022001Characterization 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

PathwaySourceExternal ID
Purine metabolismKEGGko00230
Purine metabolismKEGGhsa00230
Morphine addictionKEGGhsa05032
Morphine addictionKEGGko05032
HemostasisREACTOMER-HSA-109582
Platelet homeostasisREACTOMER-HSA-418346
Nitric oxide stimulates guanylate cyclaseREACTOMER-HSA-392154
cGMP effectsREACTOMER-HSA-418457
Signal TransductionREACTOMER-HSA-162582
Signaling by GPCRREACTOMER-HSA-372790
GPCR downstream signalingREACTOMER-HSA-388396
G alpha (s) signalling eventsREACTOMER-HSA-418555

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
203517142011Poor replication of candidate genes for major depressive disorder using genome-wide association data.92
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62
171788472006Adrenal hyperplasia and adenomas are associated with inhibition of phosphodiesterase 11A in carriers of PDE11A sequence variants that are frequent in the population.44
171788472006Adrenal hyperplasia and adenomas are associated with inhibition of phosphodiesterase 11A in carriers of PDE11A sequence variants that are frequent in the population.44
170084082006Phosphodiesterase genes are associated with susceptibility to major depression and antidepressant treatment response.35
185596252008Phosphodiesterase 11A (PDE11A) and genetic predisposition to adrenocortical tumors.33
185596252008Phosphodiesterase 11A (PDE11A) and genetic predisposition to adrenocortical tumors.33
195498882009Functional phosphodiesterase 11A mutations may modify the risk of familial and bilateral testicular germ cell tumors.30
195498882009Functional phosphodiesterase 11A mutations may modify the risk of familial and bilateral testicular germ cell tumors.30

Citation

Rossella Libé ; Jérôme Bertherat

PDE11A (phosphodiesterase 11A)

Atlas Genet Cytogenet Oncol Haematol. 2010-01-01

Online version: http://atlasgeneticsoncology.org/gene/44448/pde11a