GeneBe

PDE4D

protein-coding

phosphodiesterase 4D, the group of Phosphodiesterases|MicroRNA protein coding host genes

Gene summary

This gene encodes one of four mammalian counterparts to the fruit fly 'dunce' gene. The encoded protein has 3',5'-cyclic-AMP phosphodiesterase activity and degrades cAMP, which acts as a signal transduction molecule in multiple cell types. This gene uses different promoters to generate multiple alternatively spliced transcript variants that encode functional proteins.[provided by RefSeq, Sep 2009]

Previous symbols:
  • DPDE3

MANE transcript

NM_001104631.2

Inheritance

AD

ClinVar variants

P:30U:224B:116

Top phenotype

Acrodysostosis 2, with or without hormone resistance

gnomAD constraint

pLI —, LoF o/e 0.08

Max pathogenic AF

—

Genomic locus

chr5:58,969,038-60,522,120

External References & Databases

Ensembl (ENSG00000113448)NCBI Gene (5144)OMIM (600129)HGNC:8783GenCCUniProt (Q08499)AlphaFoldClinVar (PDE4D)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~1,553.1 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

acrodysostosis 2 with or without hormone resistanceSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013822

Submitter: Labcorp Genetics (formerly Invitae)

acrodysostosis 2 with or without hormone resistanceDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013822

Submitter: G2P

acrodysostosis 2 with or without hormone resistanceMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0013822

Submitter: Ambry Genetics

acrodysostosisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019797

Submitter: Orphanet

acrodysostosis 2 with or without hormone resistanceSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013822

Submitter: PanelApp Australia

chromosome 5q12 deletion syndromeSUPPORTIVE

Inheritance Pattern: Unknown

Disease ID:MONDO:0014298

Submitter: Orphanet

Clinical Genomic Database (CGD)

Acrodysostosis 2, with or without hormone resistanceAD

Manifestation: Cardiovascular;Craniofacial; Endocrine; Genitourinary; Musculoskeletal; Neurologic

Intervention: Cardiovascular; Endocrine

Rationale: Individuals have been described with cardiovascular anomalies, including deep vein thrombosis, and awareness may allow early recognition and treatment; Individuals have been described with endocrine anomalies, including parathyroid hormone resistance and hypogonadism, and awareness may allow surveillance and early medical interventions

Refs: 11200992; 22464252; 22464250; 22464252; 23033274; 24203977Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PDE4D variants in ClinVar

12 Conditions Cataloged
not providedTotal: 370
Acrodysostosis 2 with or without hormone resistanceTotal: 80
Inborn genetic diseasesTotal: 61
not specifiedTotal: 43
PDE4D-related disorderTotal: 32
EBV-positive nodal T- and NK-cell lymphomaTotal: 1
Pyloric stenosisTotal: 1
Craniosynostosis syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001104631.2. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
5
clinvar
89
clinvar
6
clinvar
 100
missense
13
clinvar
17
clinvar
206
clinvar
18
clinvar
3
clinvar
 257
nonsense
5
clinvar
 5
start loss
0
frameshift
7
clinvar
 7
splice donor/acceptor (+/-2bp)
1
clinvar
 1
Total13172241079370

Highest pathogenic variant AF is 7.081842e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 57 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001104631.2RefSeqNP_001098101.115MANE Select
ENST00000340635.11EnsemblENSP00000345502.615MANE Select
NM_001165899.2RefSeqNP_001159371.116Standard
NM_001197218.2RefSeqNP_001184147.115Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
pde4dDanio rerio

Structure: head

Quality: increased size

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • cAMP signaling pathway - Homo sapiens (human)
  • Purine metabolism - Homo sapiens (human)
  • Morphine addiction - Homo sapiens (human)
  • Beta-agonist/Beta-blocker Pathway, Pharmacodynamics
  • Purine Nucleoside Phosphorylase Deficiency

Biological Process

  • regulation of heart rate
  • cAMP catabolic process
  • smooth muscle contraction
  • G protein-coupled receptor signaling pathway
  • aging

Molecular Function

  • 3',5'-cyclic-nucleotide phosphodiesterase activity
  • 3',5'-cyclic-AMP phosphodiesterase activity
  • protein binding
  • drug binding
  • enzyme binding

Cellular Component

  • centrosome
  • cytosol
  • plasma membrane
  • voltage-gated calcium channel complex
  • apical plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000340635
Coding exons
15
Length
1553083
Individuals with no LoFs
124878
Homozygous LoFs
0
Heterozygous LoFs
9
Defined
124887
p
0.0000360
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense3.751904020.4730.00002095309
Missense (PolyPhen)39152.950.254981969
Synonymous0.9531311460.9000.000007451540
Loss of Function5.23337.60.07980.00000219439

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.0000580.000058rare
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.0000630.000062rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes. {ECO:0000269|PubMed:15260978, ECO:0000269|PubMed:15576036}.;
Disease
DISEASE: Note=Genetic variations in PDE4D might be associated with susceptibility to stroke. PubMed:17006457 states that association with stroke has to be considered with caution. {ECO:0000269|PubMed:17006457}.; DISEASE: Acrodysostosis 2, with or without hormone resistance (ACRDYS2) [MIM:614613]: A pleiotropic disorder characterized by skeletal, endocrine, and neurological abnormalities. Skeletal features include brachycephaly, midface hypoplasia with a small upturned nose, brachydactyly, and lumbar spinal stenosis. Endocrine abnormalities include hypothyroidism and hypogonadism in males and irregular menses in females. Developmental disability is a common finding but is variable in severity and can be associated with significant behavioral problems. {ECO:0000269|PubMed:22464250, ECO:0000269|PubMed:22464252, ECO:0000269|PubMed:23033274, ECO:0000269|PubMed:23043190}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.345

Intolerance Scores

LoFtool
0.327
RVIS EVS
-1.38
RVIS percentile EVS
4.39

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.992

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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