Alternative titles; symbols
HGNC Approved Gene Symbol: CNGA3
Cytogenetic location: 2q11.2 Genomic coordinates (GRCh38) : 2:98,346,456-98,398,601 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q11.2 | Achromatopsia 2 | 216900 | Autosomal recessive | 3 |
Cyclic nucleotide-gated (CNG) cation channels are essential in visual and olfactory signal transduction. These proteins, CNG1 (123825) and CNG2 (300338), are encoded by 2 different genes. The CNG1 channel is activated at 40-fold higher cGMP concentrations than the CNG2 channel. Biel et al. (1994) cloned an additional member of the cGMP-gated channel family, termed CNG3, from bovine kidney. Its deduced amino acid sequence was found to be 60% and 62% identical with the CNG-channel proteins from bovine rod outer segment and bovine olfactory epithelium, respectively. Northern analysis and RT-PCR showed that the CNG3 mRNA is present in testis, kidney, and heart. Biel et al. (1994) suggested that chemotaxis of sperm cells may be controlled during fertilization by a mechanism similar to olfactory signal transduction because testis expresses members of the olfactory-receptor gene family.
In complete achromatopsia, cone photoreceptors, the retinal sensory neurons mediating color vision, seem viable but fail to generate an electrical response to light. The CNGA3 gene encodes one of a family of alpha subunits that form CNG ion channels required for sensory transduction in rod photoreceptors and in olfactory neurons. The CNG3 channel consists of CNGA3 and CNGB3 (605080) in a heterotetrameric structure of 2 alpha and 2 beta subunits (Sundin et al., 2000).
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.
Yau (1994) reviewed the expanding family of cyclic nucleotide-gated channels.
Wissinger et al. (1998) performed linkage analysis in 8 families with total colorblindness, also known as rod monochromacy or achromatopsia, an autosomal recessively inherited condition. Linkage was found with markers located at the pericentromeric region of chromosome 2. Further homozygosity mapping refined the locus to an interval of approximately 3 cM covering the locus, which they designated ACHM2. Radiation hybrid mapping of the CNGA3 gene resulted in a maximum lod score of 16.1 with marker D2S2311, which had been shown to be closely situated to the ACHM2 locus. The findings indicated that the CNGA3 gene mapped within the critical interval of the ACHM2 locus.
Kohl et al. (1998) screened the CNGA3 gene in patients from 5 families with rod monochromacy (ACHM2; 216900) linked to 2q11. In one family, affected members were homozygous for a pro163-to-leu missense mutation (P163L; 600053.0001). In a second family, homozygosity for an arg283-to-trp missense mutation was found (R283W; 600053.0002). Compound heterozygosity was found in other patients. Notably, 7 of the 8 mutations identified by Kohl et al. (1998) were in exon 7; the exceptional mutation, P163L, was located in exon 5.
Wissinger et al. (2001) screened for CNGA3 mutations in 258 independent families with hereditary cone photoreceptor disorders and found CNGA3 mutations not only in patients with the complete form of achromatopsia, but also in patients with incomplete achromatopsia and even in a few patients diagnosed with severe progressive cone dystrophy. Mutations were identified in 53 families and included 8 previously described mutations and 38 novel mutations. These mutations comprised 39 amino acid substitutions, 4 stop-codon mutations, two 1-bp insertions, and one 3-bp in-frame deletion. Most of the amino acid substitutions affected residues conserved in the CNG channel family and were clustered at the cytoplasmic face of transmembrane domains (TM) S1 and S2, in TM S4, and in the cGMP-binding domain. Four mutations, arg277 to cys (R277C; 600053.0009), arg283 to trp (R283W; 600053.0002), arg436 to trp (R435W; 600053.0010), and phe547 to leu (F547L; 600053.0006), accounted for 41.8% of all the detected mutations.
Wiszniewski et al. (2007) analyzed the CNGA3, CNGB3, and GNAT2 (139340) genes in 16 unrelated patients with autosomal recessive ACHM: 10 patients had mutations in CNGB3, 3 had mutations in CNGA3, and no coding region mutations were found in 3 patients. The authors concluded that CNGA3 and CNGB3 mutations are responsible for the substantial majority of achromatopsia.
In a study of 15 Chinese patients from 10 unrelated families with ACHM, Liang et al. (2015) identified CNGA3 mutations in 13 patients from 8 families.
In a man of Senegalese ancestry who had achromatopsia as well as features of retinitis pigmentosa (see RP93, 619845), Mejecase et al. (2019) identified homozygosity for a 2-bp deletion in the CNGA3 gene (600053.0011). The proband's 2 older brothers exhibited nonsyndromic RP, and all 3 brothers were compound heterozygous for mutations in the CC2D2A gene (612013.0010-612013.0011).
Associations Pending Confirmation
In a female patient from a consanguineous Saudi Arabian family who had been diagnosed with Leber congenital amaurosis (LCA; see 204000), Wang et al. (2011) identified homozygosity for a missense mutation in the CNGA3 gene (1579G-C; L527M) that segregated with disease in the family. The mutation, located at a conserved residue in the cGMP-binding domain, was not found in 200 controls or in the dbSNP (build 130) or 1000 Genomes Project databases. The female patient had nystagmus noted shortly after birth, and electroretinogram was nonrecordable at 10 months of age. At 2 years of age she was noted to have very sluggish pupils and no visual responses were elicited.
Hattar et al. (2003) investigated whether photoreceptor systems besides rod-cone and melanopsin participate in pupillary reflex, light-induced phase delays of the circadian clock, and period lengthening of the circadian rhythm in constant light. Using mice lacking rods and cones, Hattar et al. (2003) measured the action spectrum for phase-shifting the circadian rhythm of locomotor behavior. This spectrum matched that for the pupillary light reflex in mice of the same genotype, and that for the intrinsic photosensitivity of the melanopsin-expressing retinal ganglion cells. Hattar et al. (2003) also generated triple-knockout mice (for Gnat, 139330, Cnga3, and Opn4, 606665) in which the rod-cone and melanopsin systems were both silenced. These animals had an intact retina but failed to show any significant pupil reflex, to entrain to light/dark cycles, and to show any masking response to light. Thus, Hattar et al. (2003) concluded that the rod-cone and melanopsin systems together seem to provide all of the photic input for these accessory visual functions.
Ding et al. (2009) observed that Cnga3 protein and mRNA levels were significantly decreased in Cngb3 -/- mice; in contrast, mRNA levels of S-opsin (CBD; 303800), Gnat2, and Pde6c (600827) were unchanged relative to wildtype mice. The authors concluded that loss of CNGB3 reduces biosynthesis of CNGA3 and impairs cone CNG channel function. They suggested that downregulation of CNGA3 may contribute to the pathogenic mechanism by which CNGB3 mutations lead to human cone disease.
Kohl et al. (1998) found that affected members in a family with rod monochromacy (ACHM2; 216900) were homozygous for a C-to-T transition at nucleotide 528 of the CNGA3 gene, resulting in a pro163-to-leu (P163L) substitution.
In affected members of a family with rod monochromacy (ACHM2; 216900), Kohl et al. (1998) found homozygosity for a C-to-T transition at nucleotide 887 of the CNGA3 gene, resulting in an arg283-to-trp (R283W) substitution.
Wissinger et al. (2001) found the R283W mutation in 19 of 110 mutant alleles, including 14 alleles in 7 homozygous patients. Haplotype analysis suggested that these alleles, which were particularly frequent among patients from Scandinavia and northern Italy, have a common origin. Some of the patients homozygous for this mutation had complete achromatopsia with no detectable cone function, whereas others had incomplete achromatopsia with residual cone ERG responses and/or color vision.
Kohl et al. (1998) found that a single patient with rod monochromacy (ACHM2; 216900) was a compound heterozygote. One mutation was arg283 to gln (R283Q), involving the same codon as the arg283-to-trp mutation (600053.0002). The nucleotide change was G to A at nucleotide 888. The second allele, of maternal origin, carried a G-to-A mutation at nucleotide 1709, resulting in a gly557-to-arg (G557R) substitution (600053.0004).
For discussion of the gly557-to-arg (G557R) mutation in the CNGA3 gene that was found in compound heterozygous state in a patient with achromatopsia-2 by Kohl et al. (1998), see 600053.0003.
Kohl et al. (1998) found compound heterozygosity of mutations in the CNGA3 gene as the basis of rod monochromacy (ACHM2; 216900) in one family: thr291 to arg (T291R) and phe547 to leu (F547L; 600053.0006), where the 2 allelic mutations were caused by a C-to-G transversion at nucleotide 912 and C-to-A transversion at nucleotide 1681, respectively.
For discussion of the phe547-to-leu (F547L) mutation in the CNGA3 gene that was found in compound heterozygous state in patients with achromatopsia-2 by Kohl et al. (1998), see 600053.0005.
Wissinger et al. (2001) found the F547L mutation in 12 of 110 mutant alleles from patients from German, Dutch, Italian, Turkish, and Pakistani families. Haplotype analysis suggested multiple origins of the mutation.
Kohl et al. (1998) found compound heterozygosity for mutations in the CNGA3 gene in a sibship with 2 affected individuals with rod monochromacy (ACHM2; 216900). A C-to-T transition at nucleotide 1268 caused a substitution of tryptophan for arginine at codon 411. The second pathologic change was val529 to met (600053.0008).
In 2 sibs with rod monochromacy (ACHM2; 216900), Kohl et al. (1998) identified compound heterozygosity at the CNGA locus: one allele carried the arg411-to-trp mutation (600053.0007); the other allele carried 2 changes, thr153 to met and val529 to met (V529M), of which the V529M appeared to be the pathologic change. The V529M mutation was said to be caused by a G-to-A transition at nucleotide 1625.
Zelinger et al. (2010) performed mutation analysis of more than 700 families from the Israeli and Palestinian populations with inherited retinal diseases and identified the V529M mutation, caused by a 1585G-A transition, in 10 of 30 families with achromatopsia, including 6 Arab Muslim families and 4 Oriental Jewish families. Mutation carrier frequencies were estimated at 0.8% and 1%, respectively. In addition, V529M was identified in 3 previously unreported Christian European families. The European patients were all compound heterozygous for V529M and another CNGA3 mutation, whereas most of the Arab Muslim and Jewish patients were homozygous for V529M. Haplotype analysis of mutation-bearing chromosomes from Middle Eastern and European patients revealed a shared Muslim-Jewish haplotype, which was different from the haplotypes detected in European patients, indicating a recurrent mutation stratified by a Jewish-Muslim founder effect. Microsatellite analysis of a 21.5-cM interval including CNGA3 and the adjacent chromosome 2 centromere revealed a unique and extremely rare haplotype associated with the V529M mutation. The shared mutation was calculated to have arisen about 200 generations earlier, in an ancient common ancestor who lived approximately 5,000 years ago.
In patients with rod monochromacy (ACHM2; 216900), Wissinger et al. (2001) identified a C-to-T transition at nucleotide 829 of the CNGA3 gene, resulting in an arg277-to-cys (R277C) substitution; the mutation was found in 9 of 110 mutant alleles.
In patients with rod monochromacy (ACHM2; 216900), Wissinger et al. (2001) identified a C-to-T transition at nucleotide 1306 of the CNGA3 gene, resulting in an arg436-to-trp (R436W) substitution; the mutation was found in 6 of 110 mutant alleles. All but 1 of the patients with this mutation were of German origin. Haplotype analysis suggested multiple origins of the mutation.
In a man of Senegalese ancestry (CIC02583) with achromatopsia (ACHM2; 216900), Mejecase et al. (2019) identified homozygosity for a 2-bp deletion (c.1235_1236del; chr2.98396405_98396406del, GRCh38) in the CNGA3 gene, causing a frameshift predicted to result in a premature termination codon (Glu412ValfsTer6). The proband also had features of retinitis pigmentosa (RP93; 619845), as did his 2 older brothers (CIC02584 and CIC02585); all 3 were found to be compound heterozygous for mutations in the CC2D2A gene (612013.0010-612013.0011). The respective mutations segregated fully with disease in the family.
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Ding, X.-Q., Harry, C. S., Umino, Y., Matveev, A. V., Fliesler, S. J., Barlow, R. B. Impaired cone function and cone degeneration resulting from CNGB3 deficiency: down-regulation of CNGA3 biosynthesis as a potential mechanism. Hum. Molec. Genet. 18: 4770-4780, 2009. [PubMed: 19767295] [Full Text: https://doi.org/10.1093/hmg/ddp440]
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Wiszniewski, W., Lewis, R. A., Lupski, J. R. Achromatopsia: the CNGB3 p.T383fsX mutation results from a founder effect and is responsible for the visual phenotype in the original report of a uniparental disomy 14. Hum. Genet. 121: 433-439, 2007. [PubMed: 17265047] [Full Text: https://doi.org/10.1007/s00439-006-0314-y]
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Zelinger, L., Greenberg, A., Kohl, S., Banin, E., Sharon, D. An ancient autosomal haplotype bearing a rare achromatopsia-causing founder mutation is shared among Arab Muslims and Oriental Jews. Hum. Genet. 128: 261-267, 2010. [PubMed: 20549516] [Full Text: https://doi.org/10.1007/s00439-010-0846-z]
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]