MIM Entry: 600053
*600053 CYCLIC NUCLEOTIDE-GATED CHANNEL, ALPHA-3; CNGA3
;;CONE PHOTORECEPTOR cGMP-GATED CHANNEL;;
CYCLIC NUCLEOTIDE-GATED CHANNEL, OLFACTORY, 3; CNG3
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
Wissinger et al. (1998) performed linkage analysis in 8 families with
total colorblindness (216900), 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 rod
monochromacy families in which linkage to 2q11 had been established. 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
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
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 (216900) were homozygous for a C-to-T transition at
nucleotide 528 of the CNGA3 gene, resulting in a pro163-to-leu (P163L)
In affected members of a family with rod monochromacy (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
Kohl et al. (1998) found that a single patient with rod monochromacy
(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
See 600053.0003 and Kohl et al. (1998).
Kohl et al. (1998) found compound heterozygosity of mutations in the
CNGA3 gene as the basis of rod monochromacy (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.
See 600053.0005 and Kohl et al. (1998) Wissinger et al. (2001) found the
F547L mutation in 12 of 110 mutant alleles and 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 (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 (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 caused by a
G-to-A transition at nucleotide 1625.
In patients with rod monochromacy (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 (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.
1. Biel, M.; Zong, X.; Distler, M.; Bosse, E.; Klugbauer, N.; Murakami,
M.; Flockerzi, V.; Hofmann, F.: Another member of the cyclic nucleotide-gated
channel family, expressed in testis, kidney, and heart. Proc. Nat.
Acad. Sci. 91: 3505-3509, 1994.
2. 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.
3. Hattar, S.; Lucas, R. J.; Mrosovsky, N.; Thompson, S.; Douglas,
R. H.; Hankins, M. W.; Lem, J.; Biel, M.; Hofmann, F.; Foster, R.
G.; Yau, K.-W.: Melanopsin and rod-cone photoreceptive systems account
for all major accessory visual functions in mice. Nature 424: 75-81,
4. Kohl, S.; Marx, T.; Giddings, I.; Jagle, H.; Jacobson, S. G.; Apfelstedt-Syll a,
E.; Zrenner, E.; Sharpe, L. T.; Wissinger, B.: Total colourblindness
is caused by mutations in the gene encoding the alpha-subunit of the
cone photoreceptor cGMP-gated cation channel. Nature Genet. 19:
5. Sundin, O. H.; Yang, J. M.; Li, Y.; Zhu, D.; Hurd, J. N.; Mitchell,
T. N.; Silva, E. D.; Maumenee, I. H.: Genetic basis of total colourblindness
among the Pingelapese islanders. Nature Genet. 25: 289-293, 2000.
6. Wissinger, B.; Gamer, D.; Jagle, H.; Giorda, R.; Marx, T.; Mayer,
S.; Tippmann, S.; Broghammer, M.; Jurklies, B.; Rosenberg, T.; Jacobson,
S. G.; Sener, E. C.; and 17 others: CNGA3 mutations in hereditary
cone photoreceptor disorders. Am. J. Hum. Genet. 69: 722-737, 2001.
7. Wissinger, B.; Jagle, H.; Kohl, S.; Broghammer, M.; Baumann, B.;
Hanna, D. B.; Hedels, C.; Apfelstedt-Sylla, E.; Randazzo, G.; Jacobson,
S. G.; Zrenner, E.; Sharpe, L. T.: Human rod monochromacy: linkage
analysis and mapping of a cone photoreceptor expressed candidate gene
on chromosome 2q11. Genomics 51: 325-331, 1998.
8. 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.
9. Yau, K.-W.: Cyclic nucleotide-gated channels: an expanding new
family of ion channels. Proc. Nat. Acad. Sci. 91: 3481-3483, 1994.
10. Zhong, H.; Molday, L. L.; Molday, R. S.; Yau, K.-W.: The heteromeric
cyclic nucleotide-gated channel adopts a 3A:1B stoichiometry. Nature 420:
George E. Tiller - updated: 11/1/2010
Marla J. F. O'Neill - updated: 8/22/2007
Ada Hamosh - updated: 6/17/2003
Ada Hamosh - updated: 11/13/2002
Deborah L. Stone - updated: 11/7/2001
Victor A. McKusick - updated: 10/5/1998
Victor A. McKusick: 7/26/1994