Alternative titles; symbols
HGNC Approved Gene Symbol: PDE6C
Cytogenetic location: 10q23.33 Genomic coordinates (GRCh38) : 10:93,612,537-93,666,010 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q23.33 | Cone dystrophy 4 | 613093 | Autosomal recessive | 3 |
In the retinal rods, phosphodiesterase (PDE) is composed of an 88-kD alpha subunit (180071), an 84-kD beta subunit (180072) and two 11-kD gamma subunits (180073), while in cones PDE occurs as a homodimer of two 94-kD alpha-prime subunits (PDE6C) that are associated with 3 smaller proteins of 11, 13, and 15 kD. The 11- and 13-kD proteins are similar to the rod gamma subunits, while the 15-kD delta subunit binds to both cone and rod PDE. Li et al. (1990) cloned the bovine cone photoreceptor cGMP phosphodiesterase alpha-prime subunit (which they called PDEA2) from a retinal cDNA library using a portion of the rod cGMP PDE alpha subunit as a probe.
Piriev et al. (1995) showed that the human PDEA2 gene encodes an 858-amino acid protein that is 93% identical to the bovine sequence. The protein contains 2 cGMP binding domains and a C-terminal catalytic domain.
Feshchenko et al. (1996) likewise reported the complete cDNA sequence. It was found to be 3,455 bp in length and to encode a polypeptide of 858 amino acids and a calculated molecular mass of 99,169 Da. The deduced amino acid sequence displayed high homology to the alpha, beta, and alpha-prime subunits of bovine, human, chicken, and mouse photoreceptor PDEs.
Piriev et al. (1995) showed that the human PDEA2 gene consists of 22 exons spanning approximately 48 kb of genomic DNA. The intron-exon structure of human PDE6C is very similar to that of rod PDE6B (180072), suggesting a recent evolutionary history.
Piriev et al. (1995) mapped the PDE6C gene to 10q24 by fluorescence in situ hybridization.
Thiadens et al. (2009) identified homozygous and compound heterozygous mutations in the PDE6C gene (600827.0001-600827.0006) in affected members of 4 families with early-onset cone photoreceptor disorders, ranging from early-onset cone dystrophy (COD4; 613093) to complete achromatopsia (ACHM5; see 613093). Electroretinogram (ERG) analysis in the 2 oldest mutation-positive patients at ages 47 and 51 years, respectively, showed absent cone responses but no abnormal rod responses, and normal rod responses were also observed in the 3 patients with complete achromatopsia. Thiadens et al. (2009) concluded that rod involvement does not appear to be a major consequence of PDE6C mutations, although they noted that some dysfunction of rods may still occur later in life.
In affected members of 2 families and 2 sporadic patients with achromatopsia-5, Chang et al. (2009) identified homozygosity or compound heterozygosity for mutations in the PDE6C gene (600827.0007-600827.0013, respectively).
In cpfl1 mice, which lack cone function and show rapid degeneration of cone photoreceptors, Chang et al. (2009) performed linkage analysis and identified a 0.7-cM interval containing the candidate gene Pde6c. Comparative cDNA analysis revealed the presence of a 116-bp insertion and a 1-bp deletion in the Pde6c gene of the mutant mice; both mutations were predicted to introduce premature termination codons. At 3 weeks of age, ERGs in cpfl1 mice showed normal dark-adapted responses, whereas light-adapted responses representing cone function were virtually absent. Retinal histology revealed grossly normal morphology and layering, but as early as 3 weeks of age there was vacuolization of a small subset of cells in the photoreceptor layer with subsequent rapid, progressive depletion of cone photoreceptors. In addition, Chang et al. (2009) observed swollen and pyknotic nuclei in the inner nuclear layer; loss of cones progressed such that only very few could be detected in retinal sections of 5-month-old cpfl1 mice.
Moshiri et al. (2019) reported 4 visually impaired rhesus macaques that showed signs of achromatopsia nearly identical to those of the human condition. All 4 monkeys were homozygous for an arg565-to-gln (R565Q) mutation in Pde6c that altered a conserved residue in the catalytic domain of the enzyme, specifically within the first metal-binding motif critical for hydrolysis of cyclic nucleotides. Both parents of the affected rhesus macaques were heterozygous for the mutation, and multiple unaffected sibs were heterozygous or did not have the mutation. In transfected HEK293T cells, Pde6c with the R565Q mutation showed normal localization but profoundly diminished enzymatic activity compared with wildtype.
Cone Dystrophy 4
In 2 brothers with early-onset cone dystrophy (COD4; 613093), Thiadens et al. (2009) identified homozygosity for an 85C-T transition in exon 1 of the PDE6C gene, resulting in an arg29-to-trp (R29W) substitution at a conserved residue just upstream from the first GAF domain. The mutation was not found in 180 ethnically matched controls. The brothers had severe color vision defects with a reduced cone response on ERG when first examined at ages 6 and 7 years, respectively; they also had photophobia and nystagmus, with progressive decline in their visual acuity during their teens. ERG examination at ages 51 and 47 years, respectively, revealed no cone responses, whereas rod responses were normal.
Achromatopsia 5
In a patient (patient 15) diagnosed with achromatopsia (ACHM5; see 613093), Weisschuh et al. (2018) identified compound heterozygosity for the R29W mutation (c.85C-T, NM_006204.3) and a c.836T-C transition in the PDE6C gene, resulting in an ile279-to-thr (I279T; 600827.0014) substitution in the GAF domain.
In a sister and brother with incomplete achromatopsia (ACHM5; see 613093), born of consanguineous parents, Thiadens et al. (2009) identified homozygosity for a 967T-A transversion in exon 6 of the PDE6C gene, resulting in a tyr323-to-asn (Y323N) substitution at a fully conserved residue within the second GAF domain. The parents were each heterozygous for the mutation, which was not found in 180 ethnically matched controls. Both sibs had nystagmus but no photophobia upon initial examination at ages 7 and 10, respectively, and initial visual acuities of 0.16 (20/100) in their best eyes declined to 0.10 (20/200) over the next decade. The brother showed significantly reduced but measurable cone responses on ERG examinations at ages 10 and 20 years, with normal rod parameters.
In a 4-year-old boy with complete achromatopsia (ACHM5; see 613093), Thiadens et al. (2009) identified compound heterozygosity for a 2-bp duplication (257dupAG) in exon 1 of the PDE6C gene, predicted to result in premature termination, and a 5-bp deletion in intron 20 (2367+1delGTAAG; 600827.0004) that removes the splice donor site and is predicted to result in use of an alternative splice site causing a frameshift and premature termination of the protein. The mutations were not found in 180 ethnically matched controls. At 4 years of age, the patient had a visual acuity of 0.10 (20/200) with severe photophobia and nystagmus; ERG revealed nonrecordable cone function, with completely normal rod function.
For discussion of the 5-bp deletion in the PDE6C gene (2367+1delGTAAG) that was found in compound heterozygous state in a patient with complete achromatopsia (ACHM5; see 613093) by Thiadens et al. (2009), see 600827.0003.
In 2 sisters who were clinically diagnosed with complete achromatopsia (ACHM5; see 613093), Thiadens et al. (2009) identified compound heterozygosity for a 1363A-G transition in exon 10 of the PDE6C gene, resulting in a met455-to-val (M455V) substitution at a conserved residue located just downstream of the GAF-B domain, and a 633G-C transversion in exon 2 (600827.0006), resulting in a functionally neutral missense change. The authors noted that the mutation was predicted to completely abolish the splice donor site, resulting loss of exon 2 or inclusion of intron 2. The unaffected parents were each heterozygous for 1 of the mutations, respectively; the mutations were not found in 180 ethnically matched controls. The sisters were first examined at ages 11 and 12 years, respectively, and had severe photophobia, nystagmus, and visual acuities of 0.16 (20/100) in their best eyes, which declined to 1.10 (20/200) over the next 2 decades. ERG examinations showed no cone responses even in childhood, but normal rod responses were observed at ages 36 and 37 years, respectively.
For discussion of the 633G-C transversion in exon 2 of the PDE6C gene that was found in compound heterozygous state in 2 sisters with complete achromatopsia (ACHM5; see 613093) by Thiadens et al. (2009), see 600827.0005.
In 2 sisters with achromatopsia-5 (ACHM5; see 613093), Chang et al. (2009) identified compound heterozygosity for a 481-12T-A transversion in intron 1 and a 1483-2A-G transition in intron 11 (600827.0008) of the PDE6C gene. Their unaffected mother was heterozygous for the 481-12T-A mutation, which was not found in 100 controls, and their unaffected father and an unaffected brother were heterozygous for the 1483-2A-G mutation. Transient expression studies in COS-7 cells showed that the 481-12T-A mutation activates a cryptic splice site 10 nucleotides upstream of the genuine 3-prime splice acceptor site, resulting in a frameshift and insertion of a premature termination codon, whereas the 1483-2A-G mutation causes a complete loss of exon 12, predicting an in-frame deletion of 49 amino acid residues.
For discussion of the 1483-2A-G transition in intron 11 of the PDE6C gene that was found in compound heterozygous state in 2 sisters with achromatopsia-5 (ACHM5; see 613093) by Chang et al. (2009), see 600827.0007.
In 2 brothers with achromatopsia-5 (ACHM5; see 613093), Chang et al. (2009) identified compound heterozygosity for a 1805A-T transversion and a 2368G-A transition in the PDE6C gene, resulting in a his602-to-leu (H602L) and a glu790-to-lys (E790K; 600827.0010) substitution, respectively. Their unaffected mother was heterozygous for H602L, whereas their unaffected father and an unaffected sister were heterozygous for E790K; neither mutation was found in 100 controls. Transient expression studies in COS-7 cells showed that the 2368G-A mutation induced a partial skipping of exon 21 that predicts a frameshift mutation, but approximately 60% of transcripts were correctly spliced and harbored the E790K substitution. Analysis of cGMP hydrolysis activity in Sf9 insect cells expressing 'humanized' PDE5/PDE6 constructs containing the mutations revealed only baseline activity for H602L that was not significantly different from the untransfected control, whereas the E790K mutant had considerable residual activity that reached approximately 40% of wildtype.
For discussion of the glu790-to-lys (E790K) mutation in the PDE6C gene that was found in compound heterozygous state in 2 brothers with achromatopsia-5 (ACHM5; see 613093) by Chang et al. (2009), see 600827.0009.
In a male patient with achromatopsia-5 (ACHM5; see 613093), Chang et al. (2009) identified compound heterozygosity for an 826C-T transition and a 2457T-A transversion in the PDE6C gene, resulting in an arg276-to-ter (R276X) and a tyr819-to-ter (Y819X; 600827.0012) substitution, respectively. The mutations were found in heterozygosity in the unaffected parents, respectively.
For discussion of the tyr819-to-ter (Y819X) mutation in the PDE6C gene that was found in compound heterozygous state in a patient with achromatopsia-5 (ACHM5; see 613093) by Chang et al. (2009), see 600827.0011.
In a male patient with achromatopsia-5 (ACHM5; see 613093), Chang et al. (2009) identified homozygosity for a 1-bp insertion (1682_1683insA) in the PDE6C gene, predicted to cause a frameshift resulting in a premature termination codon at residue 561. His unaffected parents and sister were heterozygous for the mutation.
For discussion of the c.836T-C transition (c.836T-C, NM_006204.3) in the PDE6C gene, resulting in an ile279-to-thr (I279T) substitution, that was found in compound heterozygous state in a patient with achromatopsia (ACHM5; see 613093) by Weisschuh et al. (2018), see 600827.0001.
Chang, B., Grau, T., Dangel, S., Hurd, R., Jurklies, B., Sener, E. C., Andreasson, S., Dollfus, H., Baumann, B., Bolz, S., Artemyev, N., Kohl, S., Heckenlively, J., Wissinger, B. A homologous genetic basis of the murine cpfl1 mutant and human achromatopsia linked to mutations in the PDE6C gene. Proc. Nat. Acad. Sci. 106: 19581-19586, 2009. [PubMed: 19887631] [Full Text: https://doi.org/10.1073/pnas.0907720106]
Feshchenko, E. A., Andreeva, S. G., Suslova, V. A., Smirnova, E. V., Zagranichny, V. E., Lipkin, V. M. Human cone-specific cGMP phosphodiesterase alpha-prime subunit: complete cDNA sequence and gene arrangement. FEBS Lett. 381: 149-152, 1996. [PubMed: 8641425] [Full Text: https://doi.org/10.1016/0014-5793(96)00104-4]
Li, T., Volpp, K., Applebury, M. L. Bovine cone photoreceptor cGMP phosphodiesterase structure deduced from a cDNA clone. Proc. Nat. Acad. Sci. 87: 293-297, 1990. [PubMed: 2153291] [Full Text: https://doi.org/10.1073/pnas.87.1.293]
Moshiri, A., Chen, R., Kim, S., Harris, R. A., Li, Y., Raveendran, M., Davis, S., Liang, Q., Pomerantz, O., Wang, J., Garzel, L., Cameron, A., and 10 others. A nonhuman primate model of inherited retinal disease. J. Clin. Invest. 129: 863-874, 2019. [PubMed: 30667376] [Full Text: https://doi.org/10.1172/JCI123980]
Piriev, N. I., Viczian, A. S., Ye, J., Kerner, B., Korenberg, J. R., Farber, D. B. Gene structure and amino acid sequence of the human cone photoreceptor cGMP-phosphodiesterase alpha-prime subunit (PDEA2) and its chromosomal localization to 10q24. Genomics 28: 429-435, 1995. [PubMed: 7490077] [Full Text: https://doi.org/10.1006/geno.1995.1171]
Thiadens, A. A. H. J., den Hollander, A. I., Roosing, S., Nabuurs, S. B., Zekveld-Vroon, R. C., Collin, R. W. J., De Baere, E., Koenekoop, R. K., van Schooneveld, M. J., Strom, T. M., van Lith-Verhoeven, J. J. C., Lotery, A. J., van Moll-Ramirez, N., Leroy, B. P., van den Born, L. I., Hoyng, C. B., Cremers, F. P. M., Klaver, C. C. W. Homozygosity mapping reveals PDE6C mutations in parents with early-onset cone photoreceptor disorders. Am. J. Hum. Genet. 85: 240-247, 2009. [PubMed: 19615668] [Full Text: https://doi.org/10.1016/j.ajhg.2009.06.016]
Weisschuh, N., Stingl, K., Audo, I., Biskup, S., Bocquet, B., Branham, K., Burstedt, M. S., De Baere, E., De Vries, M. J., Golovleva, I., Green, A., Heckenlively, J., Leroy, B. P., Meunier, I., Traboulsi, E., Wissinger, B., Kohl, S. Mutations in the gene PDE6C encoding the catalytic subunit of the cone photoreceptor phosphodiesterase in patients with achromatopsia. Hum. Mutat. 39: 1366-1371, 2018. [PubMed: 30080950] [Full Text: https://doi.org/10.1002/humu.23606]