Alternative titles; symbols
HGNC Approved Gene Symbol: PDE6D
Cytogenetic location: 2q37.1 Genomic coordinates (GRCh38): 2:231,732,433-231,781,282 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q37.1 | Joubert syndrome 22 | 615665 | Autosomal recessive | 3 |
PDE6D is a phosphodiesterase (EC 3.1.4.17) that binds to prenyl groups and has a critical role in ciliogenesis (Humbert et al., 2012).
Ershova et al. (1997) reported that the PDE6D gene encodes a 150-amino acid protein.
Li et al. (1998) isolated both mouse and human PDE6D cDNAs from retinal libraries, using a bovine probe. They found that the predicted 150-amino acid polypeptides are unusually well conserved, with only 1 or 2 conservative substitutions in human, bovine, and mouse PDE6D. Amino acid analysis predicted that the putative mammalian protein is soluble and acidic, contains 2 N-linked glycosylation sites, and lacks hydrophobic transmembrane domains. Li et al. (1998) found that the mammalian PDE6D genes and the eyeless nematode C. elegans C27H5.1 gene have an identical intron/exon arrangement. The C. elegans C27H5.1 polypeptide shares approximately 70% amino acid similarity with the human PDE6D protein. Southern blot analysis of a variety of species suggested that the sequences of PDE6D are well conserved among vertebrate and invertebrate species.
Using Northern blot analysis, Lorenz et al. (1998) detected a 1.3-kb PDED transcript in human retina, heart, brain, placenta, liver, and skeletal muscle. A preliminary screen of all 5 exons in 20 unrelated patients with autosomal recessive retinitis pigmentosa revealed no PDED mutation. Lorenz et al. (1998) pointed out that the bovine delta subunit solubilizes the normally membrane-bound PDE and is the only subunit expressed in extraocular tissues.
Thomas et al. (2014) found ubiquitous expression of the PDE6D gene in human embryonic tissues, with highest expression in the central nervous system, renal tubules, and epithelial cells of the respiratory tract. PDE6D localized to the basal body of primary cilia in human fibroblasts.
Ershova et al. (1997) reported that the PDE6D gene contains 4 exons.
Lorenz et al. (1998) reported that the human PDED gene consists of 5 exons spanning at least 30 kb of genomic DNA.
By use of a cDNA fragment of the PDE6D gene, Ershova et al. (1997) mapped the human PDE6D gene to 2q36 by fluorescence in situ hybridization (FISH). By PCR analysis of human-hamster somatic cell hybrids, Li et al. (1998) mapped the PDE6D gene to the long arm of chromosome 2; by FISH, they localized the gene to 2q35-q36. Based on these results and known synteny, they predicted that the mouse PDE6D gene resides on chromosome 1. By FISH and radiation hybrid mapping, Lorenz et al. (1998) localized the human PDED gene to 2q37.
cGMP is the cellular second messenger involved in the transduction of visual signals in retinal rod and cone cells. Constitutively synthesized by guanylate cyclase, its level is tightly controlled by modulating its degradation by a specific phosphodiesterase (cGMP-PDE). The enzyme characterized from bovine retinal rod cells is made of a catalytic core consisting of a membrane-associated alpha-beta dimer. An inhibitory gamma subunit enables transducin to regulate the rate of cGMP degradation according to incoming visual signals. The delta subunit (PDE6D) plays a role in stabilizing the catalytic dimer from membranes (Florio et al., 1996).
Correct localization and signaling by farnesylated KRAS is regulated by the prenyl-binding protein PDED, which sustains the spatial organization of KRAS (190070) by facilitating its diffusion in the cytoplasm (Chandra et al., 2012; Zhang et al., 2004). Zimmerman et al. (2013) reported that interfering with the binding of mammalian PDED to KRAS by means of small molecules provided a novel opportunity to suppress oncogenic RAS signaling by altering its localization to endomembranes. Biochemical screening and subsequent structure-based hit optimization yielded inhibitors of the KRAS-PDED interaction that selectively bound to the prenyl-binding pocket of PDED with nanomolar affinity, inhibited oncogenic RAS signaling, and suppressed in vitro and in vivo proliferation of human pancreatic ductal adenocarcinoma cells that are dependent on oncogenic KRAS.
By tandem affinity purification, Humbert et al. (2012) found that epitope-tagged PDE6D interacted with several prenylated proteins and small GTPases in HEK293 cells. Coimmunoprecipitation, mutation, and knockdown experiments with human RPE1 retinal pigment epithelium cells and mouse IMCD3 collecting duct cells revealed that PDE6D was involved in a protein network that targeted the phospholipid phosphatase INPP5E (613037) to ciliary membranes. PDE6D interacted with the prenylated, but not the soluble, form of INPP5E. The small GTPase ARL13B (608922) bound an adjacent region of INPP5E, and overexpression of ARL13B promoted release of INPP5E from PDE6D. Knockdown of ARL13B or the ciliary protein CEP164 (614848) reduced or eliminated ciliogenesis in RPE1 cells, whereas PDE6D knockdown had little effect on ciliogenesis. Humbert et al. (2012) hypothesized that PDE5D, CEP164, and ARL13B mediate sequential steps in targeting INPP5E to ciliary membranes for cilia formation.
Ismail et al. (2011) stated that PDE-delta binds to farnesylated small G proteins. They presented the 1.7-angstrom structure of human PDE-delta in complex with C-terminally farnesylated human RHEB (601293). PDE-delta assumed immunoglobulin-like beta-sandwich folds with a flexible loop and a farnesyl-binding pocket. PDE-delta interacted almost exclusively with the C-terminal farnesyl moiety of RHEB. The interaction did not require guanine nucleotide, which bound RHEB on a surface nearly opposite to the PDE-delta-binding site. Ismail et al. (2011) observed that the limited contact of PDE-delta with RHEB provides PDE-delta with relaxed specificity for farnesylated cargo proteins. PDE-delta also interacted with a second small G protein, mouse Arl2 (601175). The interaction of PDE-delta with Arl2 was dependent upon GTP and caused a conformational change in PDE-delta that closed its farnesyl-binding pocket. In solution, addition of Arl2-GTP dissociated the PDE-delta-farnesylated RHEB complex. Addition of Arl3 (604695)-GTP also caused release of farnesylated RHEB from PDE-delta. In transfected canine kidney cells, fluorescence-labeled RHEB showed endoplasmic reticulum (ER) and Golgi localization. Addition of PDE-delta relocalized RHEB into a cytoplasmic and nuclear distribution, and subsequent addition of Arl2-GTP restored RHEB localization to ER and Golgi membranes. Ismail et al. (2011) concluded that PDE-delta functions as a solubilization factor for farnesylated RHEB and that ARL2 and ARL3 act in a GTP-dependent manner as allosteric release factors for farnesylated RHEB.
In 3 sibs, born of consanguineous parents, with Joubert syndrome-22 (JBTS22; 615665), Thomas et al. (2014) identified a homozygous splice site mutation in the PDE6D gene (602676.0001). The mutation, which was found using homozygosity mapping and whole-exome sequencing, segregated with the disorder in the family. The truncated protein localized to the basal body of primary cilia in patient fibroblasts, and the morphology of primary cilia appeared normal. The mutant mRNA did not adequately rescue a knockdown zebrafish mutant, although there was some partial rescue of abnormal eye development. Coimmunoprecipitation assays showed that the mutant PDE6D protein was unable to bind to INPP5E, and that siRNA-mediated depletion of PDE6D led to a complete loss of ciliary INPP5E. Patient fibroblasts showed abnormal accumulation of INPP5E at the apical pole of epithelial tubule cells and loss of INPP5E at the cilia. These findings indicated that PDE6D is indispensable for proper ciliary INPP5E targeting via farnesylation. The mutant PDE6D protein was also unable to bind to ARL2 and ARL3. Screening of the PDE6D gene in 940 patients with variable ciliopathy syndromes did not identify any mutations.
In a male infant, born to consanguineous Lebanese parents, with JBTS22, Megarbane et al. (2019) identified a homozygous mutation in the PDE6D gene (602676.0002). The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents.
Thomas et al. (2014) found that morpholino knockdown of pde6d in zebrafish embryos resulted in microphthalmia, pericardial edema, distended and blocked renal pronephric openings, proximal tubule cysts, and disorganized retinal cell layers.
In 3 sibs, born of consanguineous parents, with Joubert syndrome-22 (JBTS22; 615665), Thomas et al. (2014) identified a homozygous G-to-A transition in intron 3 of the PDE6D gene (c.140-1G-A), resulting in the skipping of exon 3 and premature termination. The mutation, which was found using homozygosity mapping and whole-exome sequencing, segregated with the disorder in the family. The truncated protein localized to the basal body of primary cilia in patient fibroblasts, and the morphology of primary cilia appeared normal. Transcription of the mutant mRNA did not adequately rescue a knockdown zebrafish mutant, although there was some partial rescue of abnormal eye development. Coimmunoprecipitation assays showed that the mutant PDE6D protein was unable to bind to INPP5E (613037), and that siRNA-mediated depletion of PDE6D led to a complete loss of ciliary INPP5E. Patient fibroblasts showed abnormal accumulation of INPP5E at the apical pole of epithelial tubule cells and loss of INPP5E at the cilia. These findings indicated that PDE6D is indispensable for proper ciliary INPP5E targeting via farnesylation. The mutant PDE6D protein was also unable to bind to ARL2 (601175) and ARL3 (604695).
In a male infant, born to consanguineous Lebanese parents, with Joubert syndrome-22 (JBTS22; 615665), Megarbane et al. (2019) identified a homozygous 1-bp insertion (c.367_368insG, NM_002601.3) in exon 4 of the PDE6D gene, predicted to result in a frameshift and premature termination (Leu123CysfsTer13). The mutation was predicted to remove the last 16 amino acids of the protein, which are in a conserved region associated with protein localization to the plasma membrane. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. It was not present in the dbSNP, 1000 Genomes Project, and gnomAD databases or in an in-house database of 715 Arab individuals.
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Humbert, M. C., Weihbrecht, K., Searby, C. C., Li, Y., Pope, R. M., Sheffield, V. C., Seo, S. ARL13B, PDE6D, and CEP164 form a functional network for INPP5E ciliary targeting. Proc. Nat. Acad. Sci. 109: 19691-19696, 2012. [PubMed: 23150559] [Full Text: https://doi.org/10.1073/pnas.1210916109]
Ismail, S. A., Chen, Y.-X., Rusinova, A., Chandra, A., Bierbaum, M., Gremer, L., Triola, G., Waldmann, H., Bastiaens, P. I. H., Wittinghofer, A. Arl2-GTP and Arl3-GTP regulate a GDI-like transport system for farnesylated cargo. Nature Chem. Biol. 7: 942-949, 2011. [PubMed: 22002721] [Full Text: https://doi.org/10.1038/nchembio.686]
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Megarbane, A., Hmaimess, G., Bizzari, S., El-Bazzal, L., Al-Ali, M. T., Stora, S., Delague, V., El-Hayek, S. A novel PDE6D mutation in a patient with Joubert syndrome type 22 (JBTS22). Europ. J. Med. Genet. 62: 103576, 2019. Note: Electronic Article. [PubMed: 30423442] [Full Text: https://doi.org/10.1016/j.ejmg.2018.11.010]
Thomas, S., Wright, K. J., Le Corre, S., Micalizzi, A., Romani, M., Abhyankar, A., Saada, J., Perrault, I., Amiel, J., Litzler, J., Filhol, E., Elkhartoufi, N., and 16 others. A homozygous PDE6D mutation in Joubert syndrome impairs targeting of farnesylated INPP5E protein to the primary cilium. Hum. Mutat. 35: 137-146, 2014. [PubMed: 24166846] [Full Text: https://doi.org/10.1002/humu.22470]
Zhang, H., Liu, X., Zhang, K., Chen, C.-K., Frederick, J. M., Prestwich, G. D., Baehr, W. Photoreceptor cGMP phosphodiesterase delta subunit (PDE-delta) functions as a prenyl-binding protein. J. Biol. Chem. 279: 407-413, 2004. [PubMed: 14561760] [Full Text: https://doi.org/10.1074/jbc.M306559200]
Zimmerman, G., Papke, B., Ismail, S., Vartak, N., Chandra, A., Hoffmann, M., Hahn, S. A., Triola, G., Wittinghofer, A., Bastiaens, P. I. H., Waldmann, H. Small molecule inhibition of the KRAS-PDE-delta interaction impairs oncogenic KRAS signalling. Nature 497: 638-642, 2013. [PubMed: 23698361] [Full Text: https://doi.org/10.1038/nature12205]