Alternative titles; symbols
HGNC Approved Gene Symbol: PDE2A
Cytogenetic location: 11q13.4 Genomic coordinates (GRCh38): 11:72,576,141-72,674,422 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q13.4 | Intellectual developmental disorder with paroxysmal dyskinesia or seizures | 619150 | Autosomal recessive | 3 |
The PDE2A gene encodes a phosphodiesterase that catalyzes the hydrolysis/degradation of both cGMP and cAMP. PDE2A shows high expression in the brain, particularly in medium spiny neurons in the striatum (summary by Salpietro et al., 2018).
Rosman et al. (1997) cloned a cDNA corresponding to human PDE2A. The PDE2A gene encodes a 941-amino acid polypeptide with a predicted molecular mass of 106 kD. The protein sequence is 90% identical to bovine and rat PDE2A sequences. Northern blot analysis showed that PDE2A was expressed as a 4.2-kb mRNA at varying levels in all human tissues tested, with highest expression in brain. Expression studies revealed that PDE2A hydrolyzes cAMP and cGMP and is inhibited by the PDE2A-specific inhibitor EHNA.
Using Western blot analysis, Sadhu et al. (1999) found that PDE2A was expressed in all human tissues examined. Expression was high in neocortex and lower in aorta, cerebellum, heart, kidney, lung, pulmonary artery, and skeletal muscle. Immunocytochemical analysis revealed expression of PDE2A in capillary and venous endothelial cells in human renal, cardiac, and hepatic tissues, as well as in microvessel endothelial cells in skin, brain, and aorta. PDE2A expression was not detected in arterial endothelial cells in any intact tissues studied. PDE2A immunostaining appeared to be cytoplasmic or perinuclear.
Salpietro et al. (2018) found expression of the PDE2A gene in various human and mouse brain regions, with high expression in medium spiny neurons of the striatum, cortex, and hippocampus.
Stumpf (2021) mapped the PDE2A gene to chromosome 11q13.4 based on an alignment of the PDE2A sequence (GenBank BC040974) with the genomic sequence (GRCh38).
In a 12-year-old boy, born of possibly distantly related parents from the Canary Island of Tenerife, with intellectual developmental disorder with paroxysmal dyskinesia or seizures (IDDPADS; 619150), Salpietro et al. (2018) identified a homozygous missense mutation in the PDE2A gene (D480G; 602658.0001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was filtered against public databases and was not found in an in-house exome database. In vitro functional expression studies showed that the mutation caused markedly decreased cGMP and cAMP hydrolysis compared to controls, consistent with a loss-of-function effect, likely leading to increased cAMP and cGMP, which are intracellular signaling molecules. The authors noted that other dyskinetic/chorea movement disorders have been associated with mutations in genes involved in cAMP or cGMP metabolism, suggesting a common pathogenetic mechanism (see, e.g., PDE10A, 610652). Genetic screening of 62 additional patients with a similar disorder did not identify any PDE2A mutations, suggesting that it may be a rare cause of the disorder.
In 3 patients from 2 unrelated families with IDDPADS, Doummar et al. (2020) identified homozygous or compound heterozygous mutations in the PDE2A gene (602658.0002-602658.0004). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. None were present in public databases, including gnomAD. Functional studies of the variants were not performed, but all were predicted to result in a loss of function. Patient fibroblasts showed an abnormal and disorganized mitochondrial network, suggesting an imbalance between mitochondrial fission and fusion mechanisms.
In 2 affected sisters, born of consanguineous Iraqi parents, with IDDPADS, Haidar et al. (2020) identified a homozygous splice site mutation in the PDE2A gene (602658.0005). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in public databases. The mutation occurred in a region of shared homozygosity. Aside from the confirmation of the splicing defect, functional studies of the variant were not performed. Both patients had seizures, but neither had dyskinesia or chorea; 1 had ataxia.
Assenza et al. (2018) found that Pde2a -/- mice died in utero. Pde2a deletion affected heart size and led to ventricular dilatation. Pde2a -/- embryos displayed other cardiac defects, including absence of atrial trabeculation, interventricular septum (IVS) defects, hypertrabeculation and thinning of myocardial wall, and, in rare cases, overriding aorta and valve defects. IVS and hypertrabeculation defects were likely due to altered cell proliferation and increased death of cardiomyocyte precursors. Cardiomyocytes showed altered contraction rate likely caused by increased Cx43 (GJA1; 121014) expression. RT-PCR analysis revealed downregulation of T-box transcription factors (e.g., TBX2; 600747) and upregulation of Icer (123812), a cAMP-dependent transcription repressor, in Pde2a -/- heart, because T-box expression was regulated by cAMP inducers and Pde2a activity. Pharmacologic inhibition of Pde2a activity recapitulated embryonic heart defects seen in Pde2a -/- mice. Further analysis demonstrated that Pde2a was required in both early and late phases of heart development in mice.
Using computational tomography, Barbagallo et al. (2020) further characterized Pde2a -/- mouse embryos. The authors found that, in addition to cardiac defects, Pde2a -/- embryos also had liver defects, with abnormal accumulation of cAMP in liver. RT-PCR analysis showed reduced expression of hepatic markers and increased expression of stromal and endothelial markers the Pde2a -/- liver, suggesting that Pde2a contributed to hepatoblast differentiation and/or survival and inhibited stromal and endothelial cell differentiation. Pde2a -/- embryos exhibited liver hypoplasia, as absence of Pde2a increased apoptosis of hepatoblasts and endothelial and stromal cells in fetal liver. Apoptosis in liver also impaired differentiation of hematopoietic stem cells in Pde2a -/- embryos.
By measuring cAMP levels in a single neuron, Maurin et al. (2019) showed that Pde2a dysregulation was involved in physiopathology of Fmr1 (309550)-knockout (KO) mice, a model of fragile X syndrome (FXS; 300624). Fmr1-KO brain had increased Pde2a enzymatic activity, resulting in decreased levels of cAMP and cGMP. Blocking Pde2a rescued exaggerated long-term depression induced by activation of hippocampal metabotropic group I glutamate receptor (see 604473) in Fmr1-KO brain and abnormal immature dendritic spines in cultured Fmr1-KO cortical neurons, both of which are hallmarks of FXS in Fmr1-KO mice. Furthermore, inhibition of Pde2a activity rescued abnormal behavior in Fmr1-KO mice, as well as communication deficit in both Fmr1-KO mice and rats. The authors proposed that PDE2A may be a therapeutic target to treat FXS.
In a 12-year-old boy, born of possibly distantly related parents from the Canary Island of Tenerife, with intellectual developmental disorder with paroxysmal dyskinesia or seizures (IDDPADS; 619150), Salpietro et al. (2018) identified a homozygous c.1439A-G transition (c.1439A-G, NM_002599.4) in the PDE2A gene, resulting in an asp480-to-gly (D480G) substitution at a highly conserved residue in the predicted cyclic nucleotide binding pocket of the GAF-B domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was filtered against public databases and was not found in an in-house exome database. In vitro functional expression studies showed that the mutation caused markedly decreased cGMP and cAMP hydrolysis compared to controls, consistent with a loss-of-function effect. The mutation occurred in a region of homozygosity, suggesting a possible founder effect.
In 2 sibs (patients 1 and 2), born of consanguineous Moroccan parents, with intellectual developmental disorder with paroxysmal dyskinesia or seizures (IDDPADS; 619150), Doummar et al. (2020) identified a homozygous c.1180C-T transition (c.1180C-T, NM_002599.4) in the PDE2A gene, resulting in a gln394-to-ter (Q394X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in public databases, including gnomAD. Functional studies of the variant were not performed, but it was predicted to result in a complete loss of function. Patient fibroblasts showed an abnormal and disorganized mitochondrial network, suggesting an imbalance between mitochondrial fission and fusion mechanisms.
In a 26-year-old Caucasian man (patient 3) with intellectual developmental disorder with paroxysmal dyskinesia or seizures (IDDPADS; 619150), Doummar et al. (2020) identified compound heterozygous mutations in the PDE2A gene: a c.1922+5G-A transition (c.1922+5G-A, NM_002599.4) in intron 22, resulting in a splice site mutation, the skipping of exon 22, a frameshift, and premature termination (Ala618Valfs56), and a c.446C-T transition, resulting in a pro149-to-leu (P149L; 602658.0004) substitution at a highly conserved residue. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither was present in public databases, including gnomAD. Functional studies of the variants were not performed, but both were predicted to result in a loss of function. Patient fibroblasts showed an abnormal and disorganized mitochondrial network, suggesting an imbalance between mitochondrial fission and fusion mechanisms.
For discussion of the c.446C-T transition (c.446C-T, NM_002599.4) in the PDE2A gene, resulting in a pro149-to-leu (P149L) substitution, that was found in compound heterozygous state in a patient with intellectual developmental disorder with paroxysmal dyskinesia or seizures (IDDPADS; 619150) by Doummar et al. (2020), see 602658.0003.
In 2 affected sisters, born of consanguineous Iraqi parents, with intellectual developmental disorder with paroxysmal dyskinesia or seizures (IDDPADS; 619150), Haidar et al. (2020) identified a homozygous c.323+1G-A transition (c.323+1G-A, NM_002599) in intron 4 of the PDE2A gene, demonstrated to result in a splice site mutation, a frameshift, and premature termination of the protein. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in public databases. The mutation occurred in a region of shared homozygosity. Aside from the confirmation of the splicing defect, functional studies of the variant were not performed. Both patients had seizures, but neither had dyskinesia or chorea; 1 had ataxia. They were diagnosed clinically with atypical Rett syndrome (see 312750).
Assenza, M. R., Barbagallo, F., Barrios, F., Cornacchione, M., Campolo, F., Vivarelli, E., Gianfrilli, D., Auletta, L., Soricelli, A., Isidori, A. M., Lenzi, A., Pellegrini, M., Naro, F. Critical role of phosphodiesterase 2A in mouse congenital heart defects. Cardiovasc. Res. 114: 830-845, 2018. [PubMed: 29409032] [Full Text: https://doi.org/10.1093/cvr/cvy030]
Barbagallo, F., Rotilio, V., Assenza, M. R., Aguanno, S., Orsini, T., Putti, S., Isidori, A. M., Lenzi, A., Naro, F., De Angelis, L., Pellegrini, M. PDE2A is indispensable for mouse liver development and hematopoiesis. Int. J. Molec. Sci. 21: 2902, 2020. Note: Electronic Article. [PubMed: 32326334] [Full Text: https://doi.org/10.3390/ijms21082902]
Doummar, D., Dentel, C., Lyautey, R., Metreau, J., Keren, B., Drouot, N., Malherbe, L., Bouilleret, V., Courraud, J., Valenti-Hirsch, M. P., Minotti, L., Dozieres-Puyravel, B., and 16 others. Biallelic PDE2A variants: a new cause of syndromic paroxysmal dyskinesia. Europ. J. Hum. Genet. 28: 1403-1413, 2020. [PubMed: 32467598] [Full Text: https://doi.org/10.1038/s41431-020-0641-9]
Haidar, Z., Jalkh, N., Corbani, S., Abou-Ghoch, J., Fawaz, A., Mehawej, C., Chouery, E. A homozygous splicing mutation in PDE2A in a family with atypical Rett syndrome. Mov. Disord. 35: 896-899, 2020. [PubMed: 32196122] [Full Text: https://doi.org/10.1002/mds.28023]
Maurin, T., Melancia, F., Jarjat, M., Castro, L., Costa, L., Delhaye, S., Khayachi, A., Castagnola, S., Mota, E., Di Giorgio, A., Servadio, M., Drozd, M., and 9 others. Involvement of phosphodiesterase 2A activity in the pathophysiology of fragile X syndrome. Cereb. Cortex 29: 3241-3252, 2019. [PubMed: 30137253] [Full Text: https://doi.org/10.1093/cercor/bhy192]
Rosman, G. J., Martins, T. J., Sonnenburg, W. K., Beavo, J. A., Ferguson, K., Loughney, K. Isolation and characterization of human cDNAs encoding a cGMP-stimulated 3-prime,5-prime-cyclic nucleotide phosphodiesterase. Gene 191: 89-95, 1997. [PubMed: 9210593] [Full Text: https://doi.org/10.1016/s0378-1119(97)00046-2]
Sadhu, K., Hensley, K., Florio, V. A., Wolda, S. L. Differential expression of the cyclic GMP-stimulated phosphodiesterase PDE2A in human venous and capillary endothelial cells. J. Histochem. Cytochem. 47: 895-905, 1999. [PubMed: 10375378] [Full Text: https://doi.org/10.1177/002215549904700707]
Salpietro, V., Perez-Duenas, B., Nakashima, K., San Antonio-Arce, V., Manole, A., Efthymiou, S., Vandrovcova, J., Bettencourt, C., Mencacci, N. E., Klein, C., Kelly, M. P., Davies, C. H., Kimura, H., Macaya, A., Houlden, H. A homozygous loss-of-function mutation in PDE2A associated to early-onset hereditary chorea. Mov. Disord. 33: 482-488, 2018. [PubMed: 29392776] [Full Text: https://doi.org/10.1002/mds.27286]
Stumpf, A. M. Personal Communication. Baltimore, Md. 01/21/2021.