Alternative titles; symbols
HGNC Approved Gene Symbol: PDE1C
Cytogenetic location: 7p14.3 Genomic coordinates (GRCh38): 7:31,616,777-32,428,224 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7p14.3 | ?Deafness, autosomal dominant 74 | 618140 | Autosomal dominant | 3 |
Cyclic nucleotide phosphodiesterases (PDEs) catalyze hydrolysis of the cyclic nucleotides cAMP and cGMP to the corresponding nucleoside 5-prime-monophosphates. Mammalian PDEs have been classified into several families based on their biochemical properties. Members of the PDE1 family, such as PDE1C, are calmodulin (see 114180)-dependent PDEs (CaM-PDEs) that are stimulated by a calcium-calmodulin complex (Repaske et al., 1992).
By screening a hippocampus library with a bovine 61-kD CaM PDE cDNA, Loughney et al. (1996) isolated cDNAs encoding PDE1A (HCAM1; 171890) and PDE1C. They identified 2 alternatively spliced PDE1C mRNAs, HCAM3A and HCAM3B, encoding predicted proteins of 709 and 634 amino acids, respectively. The protein isoforms diverge at their C termini. Northern blot analysis revealed that HCAM3A is expressed as a 5.6-kb mRNA in heart and brain and at lower levels in several other tissues. HCAM3B is expressed as an approximately 10-kb mRNA in brain and heart and, to a lesser extent, in lung. The HCAM3B probe detected additional faint bands. Although expression of full-length HCAM3A and HCAM3B in S. cerevisiae did not result in PDE activity, an amino-truncated HCAM3A gave measurable PDE activity with high affinity for both cAMP and cGMP.
By Western blot analysis using antibodies that did not differentiate between PDE1C isoforms, Vandeput et al. (2007) observed a major band with an apparent molecular mass of 72 to 75 kD, consistent with the predicted mass of the PDE1C1 isoform, in human cardiac myocyte lysates. Immunohistochemical analysis of human cardiac myocytes revealed PDE1C1 in a striated pattern, with strong staining of cardiac Z bands and weaker staining of M lines.
Gong et al. (2003) described a large-scale screen to create an atlas of central nervous system (CNS) gene expression at the cellular level, and to provide a library of verified BAC vectors and transgenic mouse lines that could offer experimental access to CNS regions, cell classes, and pathways. They found that Lhx6 (608215) and Pde1c had tangential migratory patterns. In embryonic day-10.5 (E10.5) mouse, staining for Pde1c was seen along the dorsal ridge of the spinal cord, within the rhombic lip of the midbrain-hindbrain territory, and in the anterior aspect of the telencephalic vesicle. By E15.5, Pde1c marked a major population of dorsally migrating neurons, the external germinal layer of the fourth ventricle, and another population of dorsally migrating cells in the cerebral cortex. By postpartum day 7, Pde1c-expressing cells persisted in layer 1 of the cortex, suggesting that they are the neurons of the subpial granular layer (SGL), because these cells persist longer than pioneer neurons, which are thought to disappear by birth. Gong et al. (2003) concluded that Pde1c marks a previously unstudied cell population and provides a means to study the dynamics of the proliferation and migration of these cells.
Wang et al. (2018) examined expression of Pde1c in mouse cochlea and observed expression in the cytosol of outer and inner hair cells, colocalizing with Lamp1 (153330) in lysosomes. In addition, a diffuse and barely detectable cytosolic immunofluorescence was seen in hair cells and supporting cells.
Hartz (2010) mapped the PDE1C gene to chromosome 7p14.3 based on an alignment of the PDE1C sequence (GenBank BC022479) with the genomic sequence (GRCh37).
Vandeput et al. (2007) found that recombinant human PDE1C1 bound both cAMP and cGMP with high affinity and hydrolyzed both substrates with similar rates of catalysis. The velocity of the reaction, but not substrate affinity, was increased by Ca(2+)/calmodulin. PDE1C1 constituted the great majority of the cAMP and cGMP hydrolytic activity in soluble human myocardial fractions and the majority of the cGMP hydrolytic activity in cardiac microsomal fractions.
Using quantitative RT-PCR, Knight et al. (2016) found that Pde1c was highly expressed in adult mouse cardiac myocytes, but that it had negligible expression in fibroblasts. PDE1C expression was upregulated in mouse and human failing hearts compared with controls. In vitro analysis revealed that Pde1c deficiency or inhibition attenuated mouse cardiac myocyte death and apoptosis, which was largely dependent on cAMP/PKA (see 601639) and phosphatidylinositol 3-kinase (PI3K; see 601232)/Akt (see 164730) signaling. Pde1c deficiency also attenuated mouse cardiac myocyte hypertrophy in a PKA-dependent manner. In vivo, Pde1c-knockout mice subjected to transverse aortic constriction had attenuated myocardial hypertrophy, myocardial death, chamber dilation, and contractile dysfunction compared with wildtype mice. In addition, although Pde1c was expressed exclusively in cardiac myocytes, examination of the effects of Pde1c deficiency on TGF-beta-stimulated mouse cardiac fibroblast activation demonstrated that Pde1c in myocytes likely regulates myocyte production of secreted factor(s) important for fibroblast activation and fibrosis. Knight et al. (2016) concluded that PDE1C activation plays a causative role in pathologic cardiac remodeling and dysfunction.
In a large Chinese family segregating autosomal dominant nonsyndromic postlingual progressive deafness (DFNA74; 618140) over 5 generations, Wang et al. (2018) identified heterozygosity for a missense mutation in the PDE1C gene (A320S; 602987.0001) that segregated fully with disease in the family and was not found in controls.
Cygnar and Zhao (2009) generated Pde1c -/- mice, Pde4a (600126) -/- mice, and double-knockout Pde1c -/- Pde4a -/- mice and conducted electrophysiologic analysis of olfactory sensory neuron (OSN) responses by electroolfactogram (EOG). Loss of Pde1c was predicted to prolong response termination, but instead Pde1c -/- OSNs displayed reduced EOG amplitude, faster response termination, and slower onset kinetics. Catalytic activity assays showed that knockout of Pde1c eliminated all PDE activity from OSN cilia. Prolonged response termination and increased baseline noise were observed only in double-knockout Pde1c -/- Pde4a -/- mice, revealing that activity of either Pde1c in cilia or Pde4a outside of cilia was sufficient to allow rapid termination of the EOG response. Further analysis also demonstrated that OSN adaptation to repeated odor exposure was differently affected in Pde1c -/-, Pde4a -/-, and Pde1c -/- Pde4a -/- mice. Pde1c -/- OSNs displayed reduced sensitivity to odors and attenuated adaptation to repeated stimulation. Cygnar and Zhao (2009) suggested that PDE1C may be involved in regulating OSN sensitivity and adaptation.
In 15 affected members of a large 5-generation Chinese family with nonsyndromic postlingual progressive deafness (DFNA74; 618140), Wang et al. (2018) identified heterozygosity for a c.958G-T transversion (c.958G-T, NM_001191058) in the PDE1C gene, resulting in an ala320-to-ser (A320S) substitution at a highly conserved residue within the catalytic domain. The mutation segregated fully with disease in the family and was not found in 215 ethnically matched controls. The variant was present at low frequencies in the ExAC and gnomAD databases in East Asians only (global minor allele frequency of approximately 0.00005). Functional analysis in E. coli cells demonstrated increased PDE hydrolytic activity with the mutant compared to wildtype PDE1C, for both cAMP (10-fold) and cGMP (3-fold). Wang et al. (2018) suggested that the A320S variant enhances phosphodiesterase activity and thus decreases cAMP and cGMP levels.
Cygnar, K. D., Zhao, H. Phosphodiesterase 1C is dispensable for rapid response termination of olfactory sensory neurons. Nature Neurosci. 12: 454-462, 2009. [PubMed: 19305400] [Full Text: https://doi.org/10.1038/nn.2289]
Gong, S., Zheng, C., Doughty, M. L., Losos, K., Didkovsky, N., Schambra, U. B., Nowak, N. J., Joyner, A., Leblanc, G., Hatten, M. E., Heintz, N. A gene expression atlas of the central nervous system based on bacterial artificial chromosomes. Nature 425: 917-925, 2003. [PubMed: 14586460] [Full Text: https://doi.org/10.1038/nature02033]
Hartz, P. A. Personal Communication. Baltimore, Md. 1/11/2010.
Knight, W. E., Chen, S., Zhang, Y., Oikawa, M., Wu, M., Zhou, Q., Miller, C. L., Cai, Y., Mickelsen, D. M., Moravec, C., Small, E. M., Abe, J., Yan, C. PDE1C deficiency antagonizes pathological cardiac remodeling and dysfunction. Proc. Nat. Acad. Sci. 113: E7116-E7125, 2016. [PubMed: 27791092] [Full Text: https://doi.org/10.1073/pnas.1607728113]
Loughney, K., Martins, T. J., Harris, E. A. S., Sadhu, K., Hicks, J. B., Sonnenburg, W. K., Beavo, J. A., Ferguson, K. Isolation and characterization of cDNAs corresponding to two human calcium, calmodulin-regulated, 3-prime,5-prime-cyclic nucleotide phosphodiesterases. J. Biol. Chem. 271: 796-806, 1996. [PubMed: 8557689] [Full Text: https://doi.org/10.1074/jbc.271.2.796]
Repaske, D. R., Swinnen, J. V., Jin, S.-L. C., Van Wyk, J. J., Conti, M. A polymerase chain reaction strategy to identify and clone cyclic nucleotide phosphodiesterase cDNAs: molecular cloning of the cDNA encoding the 63-kDa calmodulin-dependent phosphodiesterase. J. Biol. Chem. 267: 18683-18688, 1992. [PubMed: 1326532]
Vandeput, F., Wolda, S. L., Krall, J., Hambleton, R., Uher, L., McCaw, K. N., Radwanski, P. B., Florio, V., Movsesian, M. A. Cyclic nucleotide phosphodiesterase PDE1C1 in human cardiac myocytes. J. Biol. Chem. 282: 32749-42757, 2007. [PubMed: 17726023] [Full Text: https://doi.org/10.1074/jbc.M703173200]
Wang, L., Feng, Y., Yan, D., Qin, L., Grati, M., Mittal, R., Li, T., Sundhari, A. K., Liu, Y., Chapagain, P., Blanton, S. H., Liao, S., Liu, X. A dominant variant in the PDE1C gene is associated with nonsyndromic hearing loss. Hum. Genet. 137: 437-446, 2018. [PubMed: 29860631] [Full Text: https://doi.org/10.1007/s00439-018-1895-y]