Database: OMIM
Entry: 600053
LinkDB: 600053
MIM Entry: 600053
  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
  of achromatopsia.
  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.
Allelic Variants:
  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:
  257-259, 1998.
  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:
  193-198, 2002.
  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
Creation Date: 
  Victor A. McKusick: 7/26/1994
Edit Dates: 
  alopez: 11/03/2010
  terry: 11/1/2010
  wwang: 8/29/2007
  terry: 8/22/2007
  alopez: 7/28/2003
  alopez: 6/18/2003
  terry: 6/17/2003
  alopez: 11/13/2002
  terry: 11/12/2002
  carol: 11/9/2001
  carol: 11/7/2001
  mgross: 5/23/2001
  cwells: 5/10/2001
  dkim: 10/12/1998
  alopez: 10/5/1998
  alopez: 7/29/1998
  alopez: 7/28/1998
  jamie: 5/16/1997
  mimadm: 7/30/1994
  jason: 7/26/1994
DBGET integrated database retrieval system