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CNGB3 gene

Overview

Gene (OMIM No.)
Function of gene/protein
  • Protein: Cyclic nucleotide-gated (CNG) channel, beta-3
  • Forms a cone-specific CNG channel with the alpha-subunit encoded by CNGA3 for phototransduction
  • The CNG channel is located in the outer segment of cone photoreceptors
Clinical phenotype
(OMIM phenotype no.)
Inheritance
  • Autosomal recessive
Ocular features
  • Nystagmus from birth/early infancy in achromatopsia; usually absent in other phenotypes
  • Photophobia
  • Variable fundal phenotype (unremarkable appearance, dull foveal reflex, macular RPE mottling, Bull’s eye maculopathy and macular atrophy)
Visual function
  • Visual impairment tends to be evident from birth/early infancy among achromats but later-onset in other phenotypes
  • Variable severity of colour vision impairment; usually absent or severely impaired in achromats
  • Reduced visual acuity but severity is variable (progressive deterioration in cone dystrophies)
Systemic features
  • No specific extraocular features
Key investigations
  • Full-field ERG (ffERG): Severely reduced cone response with normal/subnormal rod response (in achromatopsia); Progressive deterioration of photopic responses in cone dystrophies
  • ffERG responses are preserved in macular dystrophies but pattern ERG may be reduced
  • OCT: Various phenotypes that are mainly confined to the foveal and parafoveal region (continuous EZ, EZ disruptions/absence, hyporeflective zone, outer retinal atrophy with RPE loss, foveal hypoplasia)
  • FAF: normal appearance, central hyper-AF or reduced central AF signal +/- a surrounding hyper-AF ring
Molecular diagnosisNext generation sequencing
  • Targeted gene panels (retinal)
  • Whole exome sequencing
  • Whole genome sequencing
Management
Therapies under research
Further information

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Additional information

Pathogenic mutations in CNGB3 is one of the major causes of achromatopsia.[1] Together with CNGA3, they account for up to 80% of cases.[2] The most common CNGB3 genotype associated with achromatopsia is the single base pair deletion c.1148delC (found in over 70% of disease-causing alleles in CNGB3), which is highly prevalent among individuals of European descent.[1]

There are various reports of patients harbouring the missense mutation c.1208G>A (p.Arg403Gln) with variable phenotypes, ranging from achromatopsia (complete and incomplete forms) to milder phenotypes such as progressive cone dystrophies and macular dystrophies.[3-5] The latter two phenotypes are less common among CNGB3 mutants and usually have later-onset with progressive cone dysfunction (in the case of cone dystrophies). The p.Arg403Gln variant is hypothesised to be a hypomorphic allele with a digenic and triallelic inheritance pattern in a subset of patients.[6]

Using animal models, Burkard and colleagues demonstrated that homozygous p.Arg403Gln mutations are associated with a relatively mild and late-onset or subclinical retinal disease. However, the presence of a null allele in CNGA3 in conjunction with compound heterozygous or homozygous p.Arg403Gln mutations exacerbated the progressive cone dystrophy phenotype.[6]

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References

  1.  Kohl S, Varsanyi B, Antunes GA, et al. CNGB3 mutations account for 50% of all cases with autosomal recessive achromatopsia. Eur J Hum Genet. 2005;13(3):302-308
  2.  Michalakis S, Schön C, Becirovic E, Biel M. Gene therapy for achromatopsia. J Gene Med. 2017;19(3)
  3.  Michaelides M, Aligianis IA, Ainsworth JR, et al. Progressive cone dystrophy associated with mutation in CNGB3. Invest Ophthalmol Vis Sci. 2004;45(6):1975-1982
  4.  Nishiguchi KM, Sandberg MA, Gorji N, Berson EL, Dryja TP. Cone cGMP-gated channel mutations and clinical findings in patients with achromatopsia, macular degeneration, and other hereditary cone diseases. Hum Mutat. 2005;25(3):248-258
  5.  Thiadens AA, Roosing S, Collin RW, et al. Comprehensive analysis of the achromatopsia genes CNGA3 and CNGB3 in progressive cone dystrophy. Ophthalmology. 2010;117(4):825-30
  6.  Burkard M, Kohl S, Krätzig T, et al. Accessory heterozygous mutations in cone photoreceptor CNGA3 exacerbate CNG channel-associated retinopathy. J Clin Invest. 2018;128(12):5663-5675
  7.  Kohl S, Baumann B, Broghammer M, et al. 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 Mol Genet. 2000;9(14):2107-2116

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Updated on November 30, 2020
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