Alternative titles; symbols
HGNC Approved Gene Symbol: RD3
Cytogenetic location: 1q32.3 Genomic coordinates (GRCh38) : 1:211,476,522-211,492,162 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q32.3 | Leber congenital amaurosis 12 | 610612 | Autosomal recessive | 3 |
By searching databases for sequences expressed in retina and/or pineal gland, followed by PCR of an adult retina cDNA library, Lavorgna et al. (2003) cloned C1ORF36. The deduced 195-amino acid protein has a calculated molecular mass of 22.7 kD. It contains an N-terminal mitochondrial targeting signal, a possible coiled-coil domain, and 2 potential phosphorylation sites. Lavorgna et al. (2003) identified ESTs representing an alternatively spliced transcript that lacks exon 2 and encodes a protein lacking the first 128 amino acids. Other ESTs suggested the presence of alternative 5-prime exons. PCR analysis of 6 human tissues detected C1ORF36 only in retina. In situ hybridization of adult mouse retina detected expression in the outer nuclear layer, the inner nuclear layer, and the ganglion cell layer.
Lavorgna et al. (2003) determined that the C1ORF36 gene contains at least 3 exons and spans over 15.45 kb. The mouse C1orf36 gene also contains at least 3 exons.
By linkage analysis, Chang et al. (1993) mapped the mouse rd3 gene to chromosome 1, about 10 cM distal to Akp1 (alkaline phosphatase-1). Chang et al. (1993) suggested that the homologous human locus may be on chromosome 1q.
By genomic sequence analysis, Lavorgna et al. (2003) mapped the C1ORF36 gene to chromosome 1q32.3.
Friedman et al. (2006) found that mouse Rd3 is preferentially expressed in the retina and exhibits increasing expression through early postnatal development. In transiently transfected COS-1 cells, the Rd3 fusion protein showed subnuclear localization adjacent to promyelocytic leukemia gene product (PML; 102578) bodies.
By coimmunoprecipitation of mouse retinal extracts, Azadi et al. (2010) found that Rd3 bound the photoreceptor guanylate cyclases Gc1 (GUCY2D; 600179) and Gc2 (GUCY2F; 300041). They confirmed interaction of Rd3 with Gc1 in transfected HEK293 cells. A short C-terminal segment of Gc1 was required for Rd3 binding. When expressed alone in COS-7 cells, Rd3 colocalized with the endosomal recycling marker Rab11 (see RAB11A; 605570) in a pattern characteristic of intracellular vesicles, whereas Gc1 localized in a perinuclear distribution characteristic of endoplasmic reticulum (ER). When coexpressed, Gc1 was exported from the ER to endosomal vesicles containing Rd3 and Rab11. Retinal extracts from Rd3 mice (see ANIMAL MODEL) lacked Gc1 protein expression and showed reduced Gc2 protein expression compared with wildtype. The GC-activating proteins Gcap1 (GUCA1A; 600364) and Gcap2 (GUCA1B; 602275) also showed reduced expression in Rd3 mice, as well as mislocalization to the inner segment of photoreceptor cells. Azadi et al. (2010) proposed that RD3 may be an accessory protein required for vesicle trafficking of GCs from inner to outer segments of rod and cone cells and that it may modulate GC enzymatic activity.
To explore potential association of the human RD3 gene with retinopathies, Friedman et al. (2006) performed a mutation screen of 881 probands from North America, India, and Europe. In addition to several alterations of uncertain significance, they identified a homozygous alteration in the invariant G nucleotide of the RD3 exon 2 donor splice site in 2 sibs with Leber congenital amaurosis (LCA12; 610612). This mutation was predicted to result in premature termination of the RD3 protein. Friedman et al. (2006) suggested that the retinopathy-associated RD3 protein is part of subnuclear protein complexes involved in diverse processes, such as transcription and splicing.
In a large consanguineous Kurdish family with LCA mapping to chromosome 1q32, Preising et al. (2012) directly sequenced the RD3 gene and identified homozygosity for a nonsense mutation (Y60X; 180040.0002) that segregated with disease in the family. Analysis of 85 unrelated patients with severe early-onset retinal dystrophy did not reveal any more causative RD3 mutations. Preising et al. (2012) concluded that sequence changes in the RD3 gene are a very rare cause of LCA.
Using DNA samples from 852 unrelated patients ascertained worldwide with LCA or early-onset severe retinal degeneration, Perrault et al. (2013) screened the RD3 gene and identified homozygosity for 3 truncating mutations in 7 probands from consanguineous LCA families (180040.0003-180040.0005).
Exclusion Studies
By mutation analysis of the coding region of the C1ORF36 gene in 300 unrelated patients with retinitis pigmentosa (RP; see 268000) patients and unrelated unaffected individuals, Lavorgna et al. (2003) found no mutations that segregated with the disease.
Chang et al. (1993) postulated the existence of a form of retinal degeneration in humans, possibly a form of retinitis pigmentosa, homologous to a primary retinal degeneration, termed rd3, in the mouse. The retinal differentiation in the mouse proceeded postnatally through 2 weeks, and photoreceptor degeneration started by 3 weeks. The rod photoreceptor loss was essentially complete by 5 weeks, whereas remnant cone cells were seen through 7 weeks. This was the only murine homozygous retinal degeneration reported to that time in which photoreceptors were initially normal.
Using the positional candidate approach, Friedman et al. (2006) identified a C-to-T transition in the mouse Rd3 gene. The Rd3 mutation resulted in a predicted stop codon after residue 106. This change was observed in 4 Rd3 lines derived from the original collected mice but not in 9 wildtype mouse strains examined. The truncated mutant Rd3 protein was detectable in COS-1 cells but appeared to be degraded rapidly.
Canine rod-cone dysplasia type-2 (rcd2) is inherited as a simple autosomal recessive trait specifically in rough and smooth collies. Night blindness is the earliest clinical sign detected in 6-week-old rcd2 dogs, followed by retinal dysfunction and failure to develop normal rod and cone outer segments. Rcd2 dogs become functionally blind by 6 to 8 months of age. Kukekova et al. (2009) identified an insertion in the canine Rd3 gene that cosegregated with rcd2 in affected dogs. Unlike mouse and human RD3, which each have a single transcript, canine Rd3 produces 3 splice variants. The insertion only affected 1 of these variants and was predicted to alter the last 61 codons of the normal ORF and further extended the ORF.
By immunofluorescence microscopy, Molday et al. (2013) observed that strong RD3 transgene expression in a strain of Rd3-deficient mice resulted in the translocation of guanylate cyclase from the endoplasmic reticulum (ER) to rod and cone outer segments. Guanylate cyclase expression and localization coincided with the survival of rod and cone photoreceptors for at least 7 months. Molday et al. (2013) concluded that RD3 plays an essential role in the exit of guanylate cyclase from the ER and in its trafficking to photoreceptor outer segments.
In 2 sibs with Leber congenital amaurosis-12 (LCA12; 610612) from an Indian family, Friedman et al. (2006) identified a homozygous donor splice site mutation, 296+1G-A, in the RD3 gene. The change was present in heterozygous state in unaffected members of the family.
In 7 affected individuals from 4 sibships of a large consanguineous Kurdish family with Leber congenital amaurosis mapping to chromosome 1q32 (LCA12; 610612), Preising et al. (2012) identified homozygosity for a c.180C-A transversion (c.180C-A, GRCh37) in the RD3 gene, resulting in a tyr60-to-ter (Y60X) substitution predicted to truncate approximately two-thirds of the gene product. Clinical data were available for 6 of the affected individuals. The unaffected parents were all heterozygous for the mutation.
In 9 affected individuals from 5 unrelated consanguineous families (2 Moroccan, 2 Turkish, and 1 Lebanese) with Leber congenital amaurosis (LCA12; 610612), Perrault et al. (2013) identified homozygosity for a c.112C-T transition (c.112C-T, GRCh37) in exon 2 of the RD3 gene, predicted to result in an arg38-to-ter (R38X) substitution and/or to create a cryptic donor splice site resulting in a 132-amino acid protein lacking residues 38 to 99, including a putative coiled-coil domain. The mutation, which segregated with disease in each family, was not found in 151 controls or in published databases. Haplotype analysis performed in 4 of the families revealed a 1-Mb shared region present in the 2 Moroccan families and 1 of the Turkish families consistent with a founder mutation that had originated 100 to 150 generations previously. The Lebanese family carried a different haplotype.
In a 21-year-old Moroccan woman with Leber congenital amaurosis-12 (LCA12; 610612), Perrault et al. (2013) identified homozygosity for a 2-bp deletion (c.137_138delAG, GRCh37) in exon 2 of the RD3 gene, causing a frameshift predicted to result in a premature termination codon (Glu46AlafsTer83). The mutation, which segregated with disease, was not found in 151 controls or in published databases.
In a 4-year-old Mexican girl with Leber congenital amaurosis-12 (LCA12; 610612), Perrault et al. (2013) identified homozygosity for a c.136G-T transversion (c.136G-T, GRCh37) in exon 2 of the RD3 gene, predicted to result in a glu46-to-ter (E46X) substitution and/or to create a cryptic donor splice site resulting in a 141-amino acid protein lacking residues 46 to 99, including a putative coiled-coil domain. The mutation, which segregated with disease, was not found in 151 controls or in published databases.
Azadi, S., Molday, L. L., Molday, R. S. RD3, the protein associated with Leber congenital amaurosis type 12, is required for guanylate cyclase trafficking in photoreceptor cells. Proc. Nat. Acad. Sci. 107: 21158-21163, 2010. [PubMed: 21078983] [Full Text: https://doi.org/10.1073/pnas.1010460107]
Chang, B., Heckenlively, J. R., Hawes, N. L., Roderick, T. H. New mouse primary retinal degeneration (rd-3). Genomics 16: 45-49, 1993. [PubMed: 8486383] [Full Text: https://doi.org/10.1006/geno.1993.1138]
Friedman, J. S., Chang, B., Kannabiran, C., Chakarova, C., Singh, H. P., Jalali, S., Hawes, N. L., Branham, K., Othman, M., Filippova, E., Thompson, D. A., Webster, A. R., Andreasson, S., Jacobson, S. G., Bhattacharya, S. S., Heckenlively, J. R., Swaroop, A. Premature truncation of a novel protein, RD3, exhibiting subnuclear localization is associated with retinal degeneration. Am. J. Hum. Genet. 79: 1059-1070, 2006. Note: Erratum: Am. J. Hum. Genet. 80: 388 only, 2007. [PubMed: 17186464] [Full Text: https://doi.org/10.1086/510021]
Kukekova, A. V., Goldstein, O., Johnson, J. L., Richardson, M. A., Pearce-Kelling, S. E., Swaroop, A., Friedman, J. S., Aguirre, G. D., Acland, G. M. Canine RD3 mutation establishes rod-cone dysplasia type 2 (rcd2) as ortholog of human and murine rd3. Mammalian Genome 20: 109-123, 2009. [PubMed: 19130129] [Full Text: https://doi.org/10.1007/s00335-008-9163-4]
Lavorgna, G., Lestingi, M., Ziviello, C., Testa, F., Simonelli, F., Manitto, M. P., Brancato, R., Ferrari, M., Rinaldi, E., Ciccodicola, A., Banfi, S. Identification and characterization of Clorf36, a transcript highly expressed in photoreceptor cells, and mutation analysis in retinitis pigmentosa. Biochem. Biophys. Res. Commun. 308: 414-421, 2003. [PubMed: 12914764] [Full Text: https://doi.org/10.1016/s0006-291x(03)01410-4]
Molday, L. L., Djajadi, H., Yan, P., Szczygiel, L., Boye, S. L., Chiodo, V. A., Gregory-Evans, K., Sarunic, M. V., Hauswirth, W. W., Molday, R. S. RD3 gene delivery restores guanylate cyclase localization and rescues photoreceptors in the Rd3 mouse model of Leber congenital amaurosis 12. Hum. Molec. Genet. 22: 3894-3905, 2013. [PubMed: 23740938] [Full Text: https://doi.org/10.1093/hmg/ddt244]
Perrault, I., Estrada-Cuzcano, A., Lopez, I., Kohl, S., Li, S., Testa, F., Zekveld-Vroon, R., Wang, X., Pomares, E., Andorf, J., Aboussair, N., Banfi, S., and 23 others. Union makes strength: a worldwide collaborative genetic and clinical study to provide a comprehensive survey of RD3 mutations and delineate the associated phenotype. PLoS One 8: e51622, 2013. Note: Electronic Article. [PubMed: 23308101] [Full Text: https://doi.org/10.1371/journal.pone.0051622]
Preising, M. N., Hausotter-Will, N., Solbach, M. C., Friedburg, C., Ruschendorf, F., Lorenz, B. Mutations in RD3 are associated with an extremely rare and severe form of early onset retinal dystrophy. Invest. Ophthal. Vis. Sci. 53: 3463-3472, 2012. [PubMed: 22531706] [Full Text: https://doi.org/10.1167/iovs.12-9519]