|Gene (OMIM No.)|
|Function of gene/protein|
| Clinical phenotype|
(OMIM phenotype no.)
|Molecular diagnosis||Next generation sequencing|
|Therapies under research|
Pathogenic mutations in CNGB3 is one of the major causes of achromatopsia. Together with CNGA3, they account for up to 80% of cases. 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.
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.
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.
- 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
- Michalakis S, Schön C, Becirovic E, Biel M. Gene therapy for achromatopsia. J Gene Med. 2017;19(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
- 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
- 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
- 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
- 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