Alternative titles; symbols
HGNC Approved Gene Symbol: CNGA1
Cytogenetic location: 4p12 Genomic coordinates (GRCh38): 4:47,935,977-48,016,681 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4p12 | Retinitis pigmentosa 49 | 613756 | Autosomal recessive | 3 |
The CNGA1 gene encodes the alpha subunit of the rod cyclic GMP-gated cation channel, which is involved in the final stage of the phototransduction pathway (summary by Dryja et al., 1995).
Phototransduction is mediated by an enzymatic cascade that ultimately leads to the hydrolysis of cGMP. The photoreceptor cells, rods and cones, integrate and respond to cGMP hydrolysis via a cGMP-gated cation channel in the plasma membrane of the outer segment. Kaupp et al. (1989) cloned this channel from bovine retina. Dhallan et al. (1991) used the bovine sequence to isolate cDNA and genomic DNA encompassing the entire protein coding region of the human homolog.
Pittler et al. (1992) determined the primary structures of the human and mouse retinal rod cGMP-gated cation channel by analysis of cDNA clones and amplified DNA. The open reading frames predicted polypeptides of 690 and 683 residues, respectively, exhibiting 88% sequence similarity. Significant sequence similarity (59%) of the visual cGMP-gated channel to the olfactory cAMP-gated channel was pointed out. The RNA transcript was found to be 3.2 kb long in human, mouse, and dog.
Dhallan et al. (1991) assigned the human CNGA1 gene to chromosome 4 by study of somatic cell hybrids. By PCR used in connection with somatic cell hybrid DNAs, Pittler et al. (1992) mapped the CNCG gene to 4p14-q13 near the centromere. By interspecific backcross haplotype analysis, the corresponding gene in the mouse, Cncg, was mapped to a site 0.9 cM proximal to the Kit locus on chromosome 5. Griffin et al. (1993) mapped the CNCG1 gene to 4p12-cen by fluorescence in situ hybridization. It is noteworthy that the rod cGMP PDE beta polypeptide (PDEB; 180072) also maps to 4p, at 4p16.3.
The retinal rod cGMP-gated cation channel is a hetero-oligomer composed of 2 homologous subunits, alpha (CNCG1) and beta (CNCG2; 600724), each with cytoplasmic N and C termini, 6 putative transmembrane domains, and a pore region. Pittler et al. (1992) and Dhallan et al. (1992) determined the genomic structure and sequence of the 10 exons encoding the alpha subunit of the retinal rod cGMP-gated cation channel.
Dhallan et al. (1992) expressed CNCG1 in vitro and quantified its channel activity. The retinal rod cGMP-gated cation channel is involved in the last stage of the phototransduction pathway. See also CNCG3L (600724).
Zhong et al. (2002) reported the identification of a leucine zipper homology domain named CLZ (carboxy-terminal leucine zipper) that is present in the distal C terminus of CNG channel A subunits but is absent from B subunits and mediates an inter-subunit interaction. With crosslinking, nondenaturing gel electrophoresis, and analytical centrifugation, this CLZ domain was found to mediate a trimeric interaction. In addition, a mutant cone CNG channel A subunit with its CLZ domain replaced by a generic trimeric leucine zipper produced channels that behaved much like the wildtype, but less so if replaced by a dimeric or tetrameric leucine zipper. This A-subunit-only, trimeric interaction suggested that heteromeric CNG channels actually adopt a 3A:1B stoichiometry. Biochemical analysis of the purified bovine rod CNG channel confirmed this conclusion. Zhong et al. (2002) concluded that this revised stoichiometry provides a new foundation for understanding the structure and function of the CNG channel family.
Dryja et al. (1995) screened 94 unrelated patients with autosomal dominant retinitis pigmentosa (RP) and 173 unrelated patients with autosomal recessive RP for mutations in the CNCG1 gene. Five mutant sequences cosegregated with the disease among 4 unrelated families with autosomal recessive RP (RP49; 613756). Two of these were nonsense mutations early in the reading frame (glu76-to-ter, 123825.0001; and lys139-to-ter, 123825.0002) and 1 was a deletion encompassing most if not all of the transcriptional unit; these 3 alleles would not be expected to encode a functional channel. The remaining 2 mutations were a missense mutation (ser316-to-phe; 123825.0003) and a frameshift caused by a 1-bp deletion (123825.0004) that truncated the last 32 amino acids of the C terminus. The latter 2 mutations were expressed in vitro and found to encode proteins that were retained predominantly inside the cell instead of being targeted to the plasma membrane.
In Xenopus oocytes, Trudeau and Zagotta (2002) showed that CNGA1-RP, a mutant form of the CNGA1 subunit which lacks the final 37 amino acids in the C-terminal region (123825.0004), formed normally-expressed functional homomeric channels similar to wildtype. In contrast, coexpression of CNGA1-RP and CNGB1 (600724) resulted in heteromeric channels that did not convey current and were not detectable at the membrane surface, despite the presence of these subunit proteins within the cell interior. Studies revealed a protein-protein interaction between the C-terminal region of CNGA1, which is deleted in CNGA1-RP, and an N-terminal region of CNGB1. In the absence of this interaction, an exposed short N-terminal region in CNGB1 prevented membrane expression of the heteromeric channel. Trudeau and Zagotta (2002) suggested that the dysfunction of the channels leads to degeneration of rod photoreceptor cells in RP.
In a large 5-generation Pakistani family segregating autosomal recessive RP mapping to chromosome 4p12, Zhang et al. (2004) sequenced the candidate gene CNGA1 and identified a 2-bp deletion (123825.0005) that segregated fully with disease was not found in controls.
From 2 cohorts totaling 99 Japanese patients with autosomal recessive or sporadic RP, Katagiri et al. (2014) identified 5 patients with homozygous or compound heterozygous frameshift mutations in the CNGA1 gene (123825.0006-123825.0008) that were shown to segregate with disease where parental DNA was available. The authors stated that this was the first report of CNGA1 mutations in Japanese patients, and noted that the frequency (5.1%) was higher than the prevalence observed in populations of European descent.
In a 26-year-old Chinese woman with RP, Gao et al. (2019) identified compound heterozygosity for mutations in the CNGA1 gene: a 1-bp deletion (123825.0009) and a missense mutation (D208N; 123825.0010), which segregated with disease in the family. Functional analysis in transfected HEK293T cells demonstrated mislocalization of the D208N mutant compared to wildtype CNGA1.
In a large 5-generation consanguineous Indian family with early-onset RP, Kandaswamy et al. (2022) identified homozygosity for a missense mutation in the CNGA1 gene (G509R; 123825.0011) that segregated with disease and was not found in controls.
Dryja et al. (1995) noted that retinitis pigmentosa is demonstrably a genetically heterogeneous set of diseases. This was indicated by the fact that dominant, recessive, X-linked, and digenic patterns of inheritance had been found in RP families and that more than 15 separate loci had been implicated by linkage studies. Five of those 15 genes had been identified before their relation to RP was established: 2 of them encode proteins functioning in the phototransduction pathway, rhodopsin (180380) and PDEB; 2 are photoreceptor-specific proteins, peripherin/RDS (PRPH2; 179605) and ROM1 (180721); and 1 is an unconventional myosin (276903), which is mutant in a form of Usher syndrome (retinitis pigmentosa and deafness). After identification of mutations in the CNCG1 gene, approximately 80% of cases still remained without identification of the specific gene mutant in the disorder. The rhodopsin locus accounts for approximately 10% of all RP cases and the remaining 5 loci account for approximately another 10%.
Kandaswamy et al. (2022) studied mice with an ENU-induced Cnga1 Y509C mutation, corresponding to Y513C in the human CNGA1 protein. Although normal Cnga1 transcript levels were detected in mutant retinal cross-sections, Cnga1 protein was not detected. The authors noted that the mutant retinas were also immunonegative for Cngb1 (600724), indicating degradation of Cngb1 in the absence of Cnga1. Electroretinography in the mutant mice showed loss of rod responses as early as postnatal week 3, with slowly progressive loss of cone-mediated responses resulting in complete blindness after 9 months. A longitudinal study of retinal degeneration in the mutant mice over 1 year using spectral-domain optical coherence tomography revealed an initial loss of 15 to 20% of the combined thickness of the outer segment and outer nuclear layer at postnatal week 3 to 2 months of age. The thickness steadily declined over time, culminating in almost complete loss of the outer segment and outer nuclear layer at 12 months of age, with only the inner nuclear and ganglion cell layers remaining. However, at 12 months the appearance of inner nuclear layer nuclei appeared scattered, suggesting onset of secondary morphologic changes in the inner retinal layer as well. Immunolabeled cone photoreceptors showed a similar degeneration over time, with loss of the OS at 9 months and complete loss of cones at 12 months.
In their family 6829 with recessive retinitis pigmentosa (RP49; 613756), Dryja et al. (1995) found a nonsense mutation in the CNGA1 gene, glu76 to ter (E76X), in heterozygous state in 2 affected sisters and in their unaffected father. No mutation was detected in the CNCG1 gene in the maternally derived allele in the 2 affected sisters. In fact, analysis with a CNCG1 polymorphism showed that they received different alleles at this locus from their mother. It was suggested that there was a pathogenic mutation in a gene encoding another subunit of the channel protein or some other protein that interacts with the alpha subunit and that the combination of the 2 defects is the cause of retinitis pigmentosa. An alternative possibility is that this mutation is not the cause of RP in this family.
In 1 of 5 families with autosomal recessive retinitis pigmentosa (RP49; 613756), Dryja et al. (1995) found that affected individuals were compound heterozygotes for a lys139-to-ter (K139X) mutation in the CNGA1 gene, and a ser316-to-phe mutation (S316F; 123825.0003).
In 2 families with autosomal recessive retinitis pigmentosa (RP49; 613756), Dryja et al. (1995) found that affected individuals were compound heterozygotes for mutations in the CNGA1 gene, a lys139-to-ter nonsense mutation (K139X; 123825.0002) and a ser316-to-phe missense mutation (S316F) in 1, and for the S316F mutation and a mutation deleting most or all of the transcriptional unit in a second family. Dryja et al. (1995) found 1 individual with autosomal dominant RP who carried the S316F mutation heterozygously. Five available affected members of this family (6003) had been previously found to carry heterozygosity for the rhodopsin missense mutation pro347-to-leu (P347L; 180380.0002). There was no clear difference in phenotype between the relatives who carried only the rhodopsin mutation and the sibs who carried both the rhodopsin and the channel protein mutation. The authors concluded that the rhodopsin mutation was the cause of the sibs' RP and that, in addition, they carried the recessive channel protein mutation S316F by chance and without obvious effect. Dryja et al. (1995) expressed this mutation in vitro and found that the encoded protein was predominantly retained inside the cell instead of being targeted to the plasma membrane.
In 1 of 5 families with autosomal recessive retinitis pigmentosa (RP49; 613756) and mutations in the CNCG1 gene, Dryja et al. (1995) found that the affected individuals in 1 family were homozygous for a 1-bp deletion in the codon for arg654, resulting in frameshift and truncation of the last 32 amino acids in the C terminus.
In a large 5-generation Pakistani family segregating autosomal recessive retinitis pigmentosa mapping to chromosome 4p12 (RP49; 613756), Zhang et al. (2004) identified a 2-bp deletion (c.626_627delTA, NM_000087.1) in exon 8 of the CNGA1 gene, causing a frameshift predicted to result in a premature termination codon (Ser209fsTer26) with loss of 5 of 6 transmembrane helices, the cyclic nucleotide-binding domain, and the modulation phosphorylation site. The deletion segregated fully with disease in 7 affected and 15 unaffected family members, and was not found in 89 unrelated Pakistani controls.
In a 51-year-old Japanese woman (RP#029) and an unrelated 46-year-old Japanese man (RP#094) with retinitis pigmentosa (RP49; 613756), Katagiri et al. (2014) identified homozygosity for a 1-bp deletion (c.265delC, NM_000087) in exon 6 of the CNGA1 gene, causing a frameshift predicted to result in a premature termination codon (Leu89PhefsTer4) with loss of most of the protein structure including all 3 functional domains. A third patient, a 35-year-old Japanese woman (RP#019) was found to be compound heterozygous for the c.265delC mutation and another 1-bp deletion in exon 11 of CNGA1 (c.1429delG; 123825.0007), also causing a frameshift and a premature termination codon (Val477TyrfsTer17), with loss of the sixth transmembrane domain helix, the cGMP-binding site, and the coiled-coil CLZ domain. Her unaffected parents were each heterozygous for 1 of the deletions; parental DNA was unavailable for the other 2 probands. Haplotype analysis showed an identical haplotype for the c.265delC allele in RP#019 and both alleles in RP#029, suggesting a common ancestor for the deletion.
For discussion of the 1-bp deletion (c.1429delG, NM_000087) in the CNGA1 gene, causing a frameshift predicted to result in a premature termination codon (Val477TyrfsTer17), that was found in compound heterozygous state in a 35-year-old Japanese woman (RP#019) with retinitis pigmentosa (RP49; 613756) by Katagiri et al. (2014), see 123825.0006.
In 2 unrelated Japanese men (RP#002 and RP#021) with retinitis pigmentosa (RP49; 613756), Katagiri et al. (2014) identified homozygosity for a 1-bp deletion (c.191delG, NM_000087) in exon 5 of the CNGA1 gene, causing a frameshift predicted to result in a premature termination codon (Gly64ValfsTer29), with loss of most of the protein structure including all 3 functional domains. Haplotype analysis showed an identical haplotype for the 4 alleles in the probands, suggesting a common ancestor for the deletion. The unaffected mother of RP#002 was heterozygous for the deletion; DNA was unavailable from the other 3 parents, or from the affected sister of RP#021.
In a 26-year-old Chinese woman with retinitis pigmentosa (RP49; 613756), Gao et al. (2019) identified compound heterozygosity for mutations in the CNGA1 gene: a 1-bp deletion (c.472delG, NM_001142564.1) in exon 5, causing a frameshift predicted to result in a premature termination codon (Leu158PhefsTer4), and a c.622G-A transition in exon 9, resulting in an asp208-to-asn (D208N; 123825.0010) substitution at a highly conserved residue within an alpha-helix structure of the second transmembrane domain. Sanger sequencing confirmed the mutations and their presence in heterozygosity in the proband's unaffected parents. Functional analysis in transfected HEK293T cells showed expression of the D208N mutant at levels similar to that of wildtype CNGA1, but unlike wildtype protein, the mutant did not localize to cellular protrusions. Immunoblot analysis showed that the amount of mutant protein was reduced in both total and membrane protein fractions.
For discussion of the c.622G-A transition (c.622G-A, NM_000087.3) in exon 9 of the CNGA1 gene, resulting in an asp208-to-asn (D208N) substitution, that was found in compound heterozygous state in a 26-year-old Chinese woman with retinitis pigmentosa (RP49; 613756) by Gao et al. (2019), see 123825.0009. Gao et al. (2019) noted that this mutation is numbered c.829G-A, D277N according to sequence NM_001142564.1.
By targeted retinal panel sequencing in a 22-year-old Indian man from a 5-generation consanguineous family (DKRRP2) with early-onset retinitis pigmentosa (RP49; 613756), Kandaswamy et al. (2022) identified homozygosity for a c.1525G-A transition (c.1525G-A, NM_001379270.1) in the CNGA1 gene, resulting in a gly509-to-arg (G509R) substitution. The authors noted that this variant is numbered c.1537G-A, G513R according to sequence NM_000087.3. PCR-based direct sequencing confirmed the mutation and its segregation with disease in the family: an affected brother and sister, the proband's cousins, were homozygous for the substitution, whereas his unaffected parents, brother, aunt, and nephew were heterozygous for the variant, which was not found in 120 ethnically matched controls. The variant was present at very low frequency in the gnomAD database (0.000008029 among exomes, 0.00001972 among genomes), and only in heterozygosity. In a mouse model with a Y509C change in Cnga1, corresponding to Y513 in the human CNGA1 protein, Kandaswamy et al. (2022) detected no Cnga1 signal in mutant retinas, which showed marked thinning of the outer nuclear layer. Electroretinography in the mutant mice showed loss of rod responses as early as postnatal week 3, with slowly progressive loss of cone-mediated responses resulting in complete blindness after 9 months.
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Gao, Q., Liu, Y., Lei, X., Deng, Q., Tong, Y., Du, L., Shen, Y. A novel CNGA1 gene mutation (c.G622A) of autosomal recessive retinitis pigmentosa leads to the CNGA1 protein reduction on membrane. Biochem. Genet. 57: 540-554, 2019. [PubMed: 30652268] [Full Text: https://doi.org/10.1007/s10528-019-09907-3]
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Katagiri, S., Akahori, M., Sergeev, Y., Yoshitake, K., Ikeo, K., Furuno, M., Hayashi, T., Kondo, M., Ueno, S., Tsunoda, K., Shinoda, K., Kuniyoshi, K., Tsurusaki, Y., Matsumoto, N., Tsuneoka, H., Iwata, T. Whole exome analysis identifies frequent CNGA1 mutations in Japanese population with autosomal recessive retinitis pigmentosa. PLoS One 9: e108721, 2014. [PubMed: 25268133] [Full Text: https://doi.org/10.1371/journal.pone.0108721]
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Zhang, Q., Zulfiqar, F., Riazuddin, S. A., Xiao, X., Ahmad, Z., Riazuddin, S., Hejtmancik, J. F. Autosomal recessive retinitis pigmentosa in a Pakistani family mapped to CNGA1 with identification of a novel mutation. Molec. Vision 10: 884-889, 2004. [PubMed: 15570217]
Zhong, H., Molday, L. L., Molday, R. S., Yau, K.-W. The heteromeric cyclic nucleotide-gated channel adopts a 3A:1B stoichiometry. Nature 420: 193-198, 2002. [PubMed: 12432397] [Full Text: https://doi.org/10.1038/nature01201]