Alternative titles; symbols
HGNC Approved Gene Symbol: PDE6G
Cytogenetic location: 17q25.3 Genomic coordinates (GRCh38): 17:81,650,459-81,663,127 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q25.3 | Retinitis pigmentosa 57 | 613582 | Autosomal recessive | 3 |
Cyclic GMP-phosphodiesterase (PDE) plays a key role in the normal functioning of retinal rod photoreceptor cells. The enzyme is composed of alpha (PDE6A; 180071)- and beta (PDE6B; 180072)-catalytic subunits and 2 identical gamma (PDE6G) subunits (Tuteja et al., 1990).
From human retina, Tuteja et al. (1990) cloned full-length PDE6G cDNA, encoding in a predicted 87-amino acid protein that was highly homologous to bovine and mouse Pde6g. Comparison of the deduced amino acid sequences from 3 species indicated evolutionary conservation. The cDNA encodes a 1.0-kb mRNA. Dvir et al. (2010) noted that the PDE6G domains in charge of transducin binding (thr67 to ile87) and PDE6A/PDE6B inhibition (asn74 to ile87) are located in the C terminus and are overlapping.
Dvir et al. (2010) noted that the PDE6G gene contains 4 exons with a noncoding exon 1.
By Southern analysis of human/mouse somatic cell hybrids and by in situ hybridization, Tuteja et al. (1990) assigned the PDE6G gene to chromosome 17 and probably to the 17q21.1 region.
By isotopic in situ hybridization, Dollfus et al. (1993) assigned PDE6G to a more distal location on chromosome 17q25. Linkage analysis using DNA markers confirmed the localization; a maximum lod score of 6.52 with no recombination was found for linkage of PDE6G and D17S24.
Cotran et al. (1991) confirmed the assignment to chromosome 17. The localization of the PDE6G gene to human chromosome 17 is consonant with the assignment of the mouse gene to chromosome 11 (Danciger et al., 1989). The chromosome 11 location eliminated Pde6g as a candidate gene for rd, a retinal degeneration of mice that maps to mouse chromosome 5; rd was subsequently shown to be caused by mutation in the beta subunit (180072).
Tsang et al. (1996) reported that levels of cGMP were initially increased in retinas of homozygous PDE-gamma mutant mice. By the time the mutants were 3 months of age, the retinal cGMP levels decreased, indicating that the cGMP concentration in homogenates was primarily due to photoreceptor cells of the retina. They postulated that high cGMP concentrations may keep cGMP gated cationic channels open continuously and lead to excessive energy load on the rod receptors, resulting in degeneration. Tsang et al. (1996) suggested that an interaction between the PDE-gamma and PDE-alpha/beta subunit is essential for proper activation of PDE and that all 3 subunits may be essential for assembly of a stable, active holoenzyme.
Heterotrimeric guanosine 5-prime-triphosphate (GTP)-binding proteins (G proteins) are deactivated by hydrolysis of the GTP that they bind when activated by transmembrane receptors. Transducin (see 189970), the G protein that relays visual excitation from rhodopsin (180380) to the phosphodiesterase in retinal photoreceptors, must be deactivated for the light response to recover. Tsang et al. (1998) demonstrated that a point mutation of the Pdeg gene that resulted in substitution of alanine for tryptophan-70 (trp70 to ala) impaired transducin-PDE interactions and slowed the recovery rate of the flash response in transgenic mouse rods. These results indicated that the normal deactivation of transducin in vivo requires the G protein to interact with its target enzyme.
Cotran et al. (1991) cloned a cDNA corresponding to PDEG and used it to search for mutations in patients with autosomal dominant, autosomal recessive, or 'isolated case' retinitis pigmentosa (RP) (see 268000), and Usher syndrome type I (see 276900). No gene deletions or rearrangements were detected in any patient by Southern blot analysis. They also found no linkage disequilibrium when they used RFLPs of the PDEG gene to analyze the genomic DNA of large sets of unrelated patients with these forms of retinitis pigmentosa. In addition, 1 autosomal dominant, 3 autosomal recessive, and 2 Usher syndrome type I pedigrees showed no cosegregation of the disease locus with the PDEG locus.
In an extended Israeli Muslim Arab pedigree segregating autosomal recessive RP mapping to chromosome 17q25.3 (RP57; 613582), Dvir et al. (2010) sequenced the candidate PDE6G gene and identified homozygosity for a splice site mutation in affected individuals (180073.0001); all unaffected family members were heterozygotes or carried 2 wildtype alleles. The authors analyzed PDE6G in 119 unrelated Israeli patients with RP and Leber congenital amaurosis (LCA; see 204000) but found no mutations; in addition, analysis of homozygosity mapping data from 90 unrelated retinitis pigmentosa and LCA patients from consanguineous Israeli families indicated that 4 had homozygous regions harboring PDE6G, but sequencing revealed no mutations. Dvir et al. (2010) stated that these negative results from 209 RP and LCA patients indicate that PDE6G mutations are very rare and that their contribution to the overall prevalence of RP and/or LCA in the Israeli population is minor.
Tsang et al. (1996) used a gene-targeting approach to disrupt the mouse PDE-gamma gene. The mutation resulted in a rapid retinal degeneration resembling human retinitis pigmentosa. In homozygous mutant mice, reduced rather than increased PDE activity was apparent; the PDE-alpha/beta dimer was formed but lacked hydrolytic activity.
Salchow et al. (1999) suggested that mice with an alanine substitution for tryptophan at position 70 in the Pdeg molecule (W70A) represent a model of stationary nyctalopia (see 310500) that can be recognized by its unusual features on corneal electroretinogram.
In 6 affected individuals from 3 sibships of an extended Israeli Muslim Arab pedigree segregating autosomal recessive retinitis pigmentosa (RP57; 613582), Dvir et al. (2010) identified homozygosity for a G-to-T transversion (187+1G-T) in the conserved donor splice site of intron 3 of the PDE6G gene. In vitro splicing assay showed that the mutation resulted in activation of a cryptic donor splice site, predicted to replace the last 25 amino acids, including the transducin binding and PDE6A/PDE6B inhibiting regions, with 52 irrelevant amino acids and yield a 114-amino acid mutant protein. All unaffected family members were heterozygotes or carried 2 wildtype alleles. No carriers of the splice site mutation were found among 256 Muslim Israeli controls, including 135 Muslim Arabs from northern Israel, 70 Muslim Arabs from central Israel, and 51 Bedouins. However, the mutation was detected in heterozygosity in 7 (8.3%) of 84 randomly selected adults from the same village in which the RP57 family resides, indicating that it represents a founder mutation in that village.
Cotran, P. R., Bruns, G. A. P., Berson, E. L., Dryja, T. P. Genetic analysis of patients with retinitis pigmentosa using a cloned cDNA probe for the human gamma subunit of cyclic GMP phosphodiesterase. Exp. Eye Res. 53: 557-564, 1991. [PubMed: 1683837] [Full Text: https://doi.org/10.1016/0014-4835(91)90213-x]
Danciger, M., Tuteja, N., Kozak, C. A., Farber, D. B. The gene for the gamma-subunit of retinal cGMP-phosphodiesterase is on mouse chromosome 11. Exp. Eye Res. 48: 303-308, 1989. [PubMed: 2538340] [Full Text: https://doi.org/10.1016/s0014-4835(89)80079-x]
Dollfus, H., Mattei, M.-G., Rozet, J.-M., Delrieu, O., Munnich, A., Kaplan, J. Physical and genetic localization of the gamma subunit of the cyclic GMP phosphodiesterase on the long arm of chromosome 17 (17q25). Genomics 17: 526-528, 1993. [PubMed: 8406511] [Full Text: https://doi.org/10.1006/geno.1993.1364]
Dvir, L., Srour, G., Abu-Ras, R., Miller, B., Shalev, S. A., Ben-Yosef, T. Autosomal-recessive early-onset retinitis pigmentosa caused by a mutation in PDE6G, the gene encoding the gamma subunit of rod cGMP phosphodiesterase. Am. J. Hum. Genet. 87: 258-264, 2010. [PubMed: 20655036] [Full Text: https://doi.org/10.1016/j.ajhg.2010.06.016]
Salchow, D. J., Gouras, P., Doi, K., Goff, S. P., Schwinger, E., Tsang, S. H. A point mutation (W70A) in the rod PDE-gamma gene desensitizing and delaying murine rod photoreceptors. Invest. Ophthal. Vis. Sci. 40: 3262-3267, 1999. [PubMed: 10586951]
Tsang, S. H., Burns, M. E., Calvert, P. D., Gouras, P., Baylor, D. A., Goff, S. P., Arshavsky, V. Y. Role for the target enzyme in deactivation of photoreceptor G protein in vivo. Science 282: 117-121, 1998. [PubMed: 9756475] [Full Text: https://doi.org/10.1126/science.282.5386.117]
Tsang, S. H., Gouras, P., Yamashita, C. K., Kjeldbye, H., Fisher, J., Farber, D. B., Goff, S. P. Retinal degeneration in mice lacking the gamma subunit of the rod cGMP phosphodiesterase. Science 272: 1026-1029, 1996. [PubMed: 8638127] [Full Text: https://doi.org/10.1126/science.272.5264.1026]
Tuteja, N., Danciger, M., Klisak, I., Tuteja, R., Inana, G., Mohandas, T., Sparkes, R. S., Farber, D. B. Isolation and characterization of cDNA encoding the gamma-subunit of cGMP phosphodiesterase in human retina. Gene 88: 227-232, 1990. [PubMed: 2161380] [Full Text: https://doi.org/10.1016/0378-1119(90)90035-p]