HGNC Approved Gene Symbol: CNGB3
Cytogenetic location: 8q21.3 Genomic coordinates (GRCh38) : 8:86,574,179-86,743,634 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8q21.3 | Achromatopsia 3 | 262300 | Autosomal recessive | 3 |
In complete achromatopsia, cone photoreceptors, the retinal sensory neurons mediating color vision, seem viable but fail to generate an electrical response to light. The 2q11 achromatopsia (ACHM2; 216900) gene (CNGA3; 600053) encodes one of a family of alpha subunits that form cyclic nucleotide-gated ion channels required for sensory transduction in rod photoreceptors and in olfactory neurons. Each of these channels is an alpha-2/beta-2 heteromeric tetramer, implying that the cone terminal also contains a beta subunit. Because a separate cone beta-subunit gene had not been found, Sundin et al. (2000) first thought that the rod beta-subunit gene CNGB1 (600724), located on 16q13, produced a transcript encoding the cone channel beta subunit. In BAC clones from the disease region, they identified sequence homologous to CNGB1 and isolated CNGB3.
Using linkage analysis, RT-PCR, and RACE, Kohl et al. (2000) identified and cloned the human CNGB3 gene, which encodes an 809-amino acid polypeptide. Northern blot analysis revealed a major transcript of 4.4 kb that is specifically expressed in the retina.
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.
Sundin et al. (2000) demonstrated that the CNGB3 gene contains at least 15 exons spanning approximately 120 kb of genomic sequence. Kohl et al. (2000) demonstrated that the human CNGB3 gene consists of 18 exons distributed over 200 kb of genomic sequence.
Sundin et al. (2000) found that the genetic basis of Pingelapese achromatopsia (ACHM3; 262300) at 8q21-q22 is biallelic mutation in the CNGB3 gene. An affected Pingelapese woman was found to be homozygous for a missense mutation (S435F; 605080.0001), and 2 brothers in another Pingelapese family were found to be compound heterozygous for 2 small frameshift deletions (c.1148delC; 605080.0002; c.319del8, 605080.0003). The findings established that ACHM3 results from a complete loss of CNGB3 function and that this gene is not required for vital processes outside the visual system. Thus, CNGA3 and CNGB3 encode the alpha and beta subunits of a single cyclic nucleotide-gated channel that is located in the photoreceptor plasma membrane and is essential for the generation of light-evoked electrical responses in the red-, green-, and blue-sensitive cones. Unlike rod photoreceptors, in which at least 29 genes are highly specific to rod function and survival, only the genes encoding these 2 channel subunits and 3 cone color pigments are known to be required by cone photoreceptors.
Kohl et al. (2000) performed analysis of the CNGB3 gene in patients with achromatopsia and identified 6 different mutations, including a missense mutation, 2 nonsense mutations, 1-bp and 8-bp deletions, and a putative splice site mutation. The 1148delC mutation was identified in several families, and in total was present on 11 of 22 disease chromosomes segregating in the families studied by Kohl et al. (2000).
In a consanguineous kindred from a rural isolate in Chile, Rojas et al. (2002) identified homozygosity for a novel frameshift mutation (605080.0005) in the CNGB3 gene in all 5 members with complete achromatopsia.
Kohl et al. (2005) analyzed the spectrum and prevalence of CNGB3 gene mutations in a cohort of 341 independent patients with achromatopsia. In 163 patients, CNGB3 mutations could be identified: 105 patients carried apparently homozygous mutations, 44 were compound heterozygous, and 14 patients had only a single mutant allele. In all, 28 different mutations were identified, including 12 nonsense mutations, 8 insertions and/or deletions, 5 putative splice site mutations, and 3 missense mutations. Several recurrent mutations were found, in particular the 1148delC mutation, which accounted for over 70% of all CNGB3 mutant alleles.
Wiszniewski et al. (2007) analyzed the CNGA3, CNGB3, and GNAT2 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 1148delC mutation was present in 10 patients and accounted for 75% (18/24) of disease-associated alleles; analysis of intragenic SNPs revealed transmission of a common haplotype consistent with a founder effect. Wiszniewski et al. (2007) concluded that CNGA3 and CNGB3 mutations are responsible for the substantial majority of achromatopsia.
Cone degeneration (cd) is an autosomal recessive canine disease, comparable to human achromatopsia, that occurs naturally in the Alaskan malamute and German shorthaired pointer breeds. Both the canine disease and its human counterpart are characterized by day-blindness and absence of retinal cone function in adults. Sidjanin et al. (2002) reported linkage of the canine cd locus to marker C9.002 on canine chromosome 29 in a series of informative outbred pedigrees derived from cd-affected Alaskan malamutes. The canine homolog of the CNGB3 gene, responsible for the human ACHM3 disease phenotype, was mapped within the zero-recombination interval for the cd locus. A deletion removing all exons of canine CNGB3 was identified in cd-affected Alaskan malamute-derived dogs. A D262N missense mutation in exon 6 within a conserved region of the same gene was detected in German shorthaired pointers affected with an allelic disorder.
Ding et al. (2009) generated Cngb3 -/- mice, and determined that cone dysfunction was apparent at postnatal day 30, the earliest time point examined. When compared with wildtype controls, photopic electroretinographic (ERG) responses were decreased by 75%, whereas scotopic ERG responses were unchanged; visual acuity was decreased by 20%, whereas contrast sensitivity was unchanged; cone density was reduced by 40%; photoreceptor apoptosis was detected; and outer segment disorganization was observed in some cones. Notably, CNGA3 (600053) protein and mRNA levels were significantly decreased in Cngb3 -/- mice; in contrast, mRNA levels of S-opsin (CBD; 303800), Gnat2 (139340), 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.
The first proband with Pingelapese blindness (ACHM3; 262300) studied by Sundin et al. (2000) was a 17-year-old woman with total colorblindness, photophobia, nystagmus, 20/200 visual acuity, and a normal-appearing retina. Electroretinography showed slightly lower than normal rod function and no detectable cone response. Sequence analysis of exons showed a C-to-T transition in exon H that caused a serine-to-phenylalanine substitution at amino acid 322. (Although originally reported as a SER322PHE mutation, additional sequencing information has corrected the amino acid position to 435.) All of the 23 affected individuals in 4 branches of the large kindred were homozygous for the mutation, and all 22 obligate carriers were heterozygous. Of the 9 unaffected, all were either heterozygous or homozygous wildtype. Kohl et al. (2000) found a similarly affected Pingelapese patient who was homozygous for the S435F mutation.
In the course of screening the CNGB3 gene in patients with achromatopsia (ACHM3; 262300) from 15 Pingelapese families, Sundin et al. (2000) found 2 brothers, aged 18 and 15 years, with total colorblindness, photophobia, nystagmus, 20/200 visual acuity, and a normal-appearing retina. Electroretinography of the older brother revealed a normal rod response and no cone response. Both brothers were healthy and of normal intelligence. One allele in the brothers carried an 8-bp deletion in exon C and the other allele carried a 1-bp deletion in exon G. Each deletion caused a frameshift in the CNGB3 coding region that eliminated all downstream protein sequence, including the critical pore, S6 transmembrane, and cGMP-binding domains. The 8-bp deletion was inherited from the father and the 1-bp deletion (T383fs) from the mother. The 1-bp deletion was found in heterozygous state in a 12-month-old girl who exhibited horizontal nystagmus, marked photophobia, a normal electroretinographic rod response, and no detectable cone response. Thus, these deletion mutations provided independent confirmation of the identity of the gene and its role in complete achromatopsia. Kohl et al. (2000) identified the 1-bp deletion in ACHM patients of different geographic origin.
In a female patient with achromatopsia and systemic features associated with maternal uniparental disomy for chromosome 14, previously reported by Pentao et al. (1992), and in 7 other unrelated patients with achromatopsia, Wiszniewski et al. (2007) identified homozygosity for the 1148delC mutation. Two other patients were found to be compound heterozygotes for the 1148delC mutation and another CNGB3 mutation. Analysis of intragenic SNPs revealed transmission of a common haplotype consistent with a founder effect.
For discussion of the 8-bp deletion (c.819del8) in the CNGB3 gene that was found in compound heterozygous state in Pingelapese brothers with achromatopsia (ACHM3; 262300) by Sundin et al. (2000), see 605080.0002.
Kohl et al. (2000) reported 2 male sibs with achromatopsia (ACHM3; 262300) who were compound heterozygous for mutation in the CNGB3 gene: a 1-bp deletion (605080.0002) and a C-to-T transition at position 607, resulting in a premature stop codon (R203X).
In a consanguineous kindred from a rural isolate in Chile, Rojas et al. (2002) identified homozygosity for 2 nucleotide changes in the CNGB3 gene in all 5 members with complete achromatopsia (ACHM3; 262300): a 488A-G transition resulting in a lys148-to-glu (K148E) substitution, and a single frameshift insertion (492insT) flanking an adenosine repeat in exon 4. The authors noted that CNGB1 subunits from human, mouse, and bovine rods contain a glutamic acid at codon 148, whereas the frameshift insertion creates 2 consecutive nonsense codons in exon 5 that would cause premature termination of protein translation. They suggested that the severely truncated polypeptide is likely to render a nonfunctional cone CNG channel and cause total colorblindness in this kindred.
This variant, previously titled MACULAR DEGENERATION, JUVENILE, has been reclassified because the pathogenicity of the variant has not been confirmed.
In an 8-year-old girl with a diagnosis of juvenile macular degeneration, Nishiguchi et al. (2005) identified a c.1405T-G transversion in the CNGB3 gene, resulting in a tyr469-to-asp (Y469D) substitution. The girl also carried the achromatopsia-null allele, the 1148delC mutation (605080.0002), but since segregation analysis could not be performed, compound heterozygosity was presumed. She had no family history of retinal disease and no visual complaints.
Hamosh (2020) noted that the Y469D variant was present in 226 of 283,474 alleles and in 1 homozygote in the gnomAD database, with an allele frequency of 0.0008001 (May 1, 2020).
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]
Hamosh, A. Personal Communication. Baltimore, Md. 5/1/2020.
Kohl, S., Baumann, B., Broghammer, M., Jagle, H., Sieving, P., Kellner, U., Spegal, R., Anastasi, M., Zrenner, E., Sharpe, L. T., Wissinger, B. Mutations in the CNGB3 gene encoding the beta-subunit of the cone photoreceptor cGMP-gated channel are responsible for achromatopsia (ACHM3) linked to chromosome 8q21. Hum. Molec. Genet. 9: 2107-2116, 2000. [PubMed: 10958649] [Full Text: https://doi.org/10.1093/hmg/9.14.2107]
Kohl, S., Varsanyi, B., Antunes, G. A., Baumann, B., Hoyng, C. B., Jagle, H., Rosenberg, T., Kellner, U., Lorenz, B., Salati, R., Jurklies, B., Farkas, A., and 16 others. CNGB3 mutations account for 50% of all cases with autosomal recessive achromatopsia. Europ. J. Hum. Genet. 13: 302-308, 2005. [PubMed: 15657609] [Full Text: https://doi.org/10.1038/sj.ejhg.5201269]
Nishiguchi, K. M., Sandberg, M. A., Gorji, N., Berson, E. L., Dryja, T. P. Cone cGMP-gated channel mutations and clinical findings in patients with achromatopsia, macular degeneration, and other hereditary cone diseases. Hum. Mutat. 25: 248-258, 2005. [PubMed: 15712225] [Full Text: https://doi.org/10.1002/humu.20142]
Pentao, L., Lewis, R. A., Ledbetter, D. H., Patel, P. I., Lupski, J. R. Maternal uniparental isodisomy of chromosome 14: association with autosomal recessive rod monochromacy. Am. J. Hum. Genet. 50: 690-699, 1992. [PubMed: 1347967]
Rojas, C. V., Maria, L. S., Santos, J. L., Cortes, F., Alliende, M. A. A frameshift insertion in the cone cyclic nucleotide gated cation channel causes complete achromatopsia in a consanguineous family from a rural isolate. Europ. J. Hum. Genet. 10: 638-642, 2002. [PubMed: 12357335] [Full Text: https://doi.org/10.1038/sj.ejhg.5200856]
Sidjanin, D. J., Lowe, J. K., McElwee, J. L., Milne, B. S., Phippen, T. M., Sargan, D. R., Aguirre, G. D., Acland, G. M., Ostrander, E. A. Canine CNGB3 mutations establish cone degeneration as orthologous to the human achromatopsia locus ACHM3. Hum. Molec. Genet. 11: 1823-1833, 2002. [PubMed: 12140185] [Full Text: https://doi.org/10.1093/hmg/11.16.1823]
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. [PubMed: 10888875] [Full Text: https://doi.org/10.1038/77162]
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]
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]