The CNGB3 gene was first reported in relation to autosomal recessive CNB3-related retinopathy in 2000 in an individual described as having achromatopsia (Sundin et. Al., 2000; PMID 10888875). Achromatopsia is characterized by photophobia, reduced visual acuity, nystagmus, and inability to discriminate between colors. Electroretinogram shows an absent cone response whereas rod function is preserved. This condition was curated under the disesae entity "CNGB3-related retinopathy".
The maximum score for genetic evidence was achieved by the addition of 5 variants (PMID:10888875, 15657609, 31544997) in this curation, however there is more evidence available in the literature. There are over 200 CNGB3 pathogenic and likely pathogenic variants listed on ClinVar (10/05/2021). In one report (PMID 15657609), a cohort of 341 unrelated patients with achromatopsia was studied which resulted in identification of disease-causing variants in 163 patients. Among them, 105 were homozygous for the variant while 44 were compound heterozygotes, 14 carried a single allele. Another study reported a deep intronic variant NM_019098.4(CNGB3):c.1663-1205G>A in-trans with pathogenic variants in 18 patients with achromatopsia, making this variant one of the most frequent variant associated with achromatopsia (PMID 31544997).
CNGB3 and CNGA3 proteins were found to be highly expressed in NRL-/- mouse retinas by western blotting and immunolabeling. Moreover, both these cone CNG channels were observed to co-localize in S and M cones (PMID 18665891). Mouse studies also supported the role of Cngb3 in cone function. A mice line with naturally occurring missense variant NM_013927:c.692G>A; p.(R231H) was studied for visual function which revealed that homozygous mice (n=12) had lost cone function while their rod function was intact (PMID 30592498). Additionally, in another knockout mouse study, homozygous null mice recapitulated achromatopsia phenotype, briefly by showing a decrease in photopic ERG responses, visual acuity, and cone density (PMID 19767295). Role of CNGB3 in cone function was also further supported by rescue studies in null mice by sub-retinal injections of AAV8(Y447,&33F) constructs. The transgenic mice showed expression of CNGB3 in cone cells and restored photopic ERG responses (PMID 32305965).
In summary, CNGB3 is definitively associated with autosomal recessive CNGB3-related retinopathy. This has been repeatedly demonstrated in both research and clinical diagnostic settings, and has been upheld over time.
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