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

Abstract

Achromatopsia is an autosomal recessive disorder featuring total colour blindness, photophobia, reduced visual acuity and nystagmus. While mutations in the CNGA3 gene on chromosome 2q11 are responsible for achromatopsia in a subset of patients, previous linkage studies have localized another achromatopsia locus, ACHM3, on chromosome 8q21. Using achromatopsia families in which CNGA3 mutations have been excluded, we refined the ACHM3 locus to a 3.7 cM region enclosed by markers D8S1838 and D8S273. Two yeast artificial chromosome (YAC) contigs covering nearly the entire ACHM3 interval were constructed. Database searches with YAC content sequences identified two overlapping high throughput genomic sequencing phase (HTGS) entries which contained sequences homologous to the murine cng6 gene encoding the putative beta-subunit of the cone photoreceptor cGMP-gated channel. Using RT-PCR and RACE, we identified and cloned the human cDNA homologue, designated CNGB3, which encodes an 809 amino acid polypeptide. Northern blot analysis revealed a major transcript of approximately 4.4 kb specifically expressed in the retina. The human CNGB3 gene consists of 18 exons distributed over approximately 200 kb of genomic sequence. Analysis of the CNGB3 gene in achromats revealed six different mutations including a missense mutation (S435F), two stop codon mutations (R203X and E336X), a 1 bp and an 8 bp deletion (1148delC and 819-826del) and a putative splice site mutation of intron 13. The 1148delC mutation was identified recurrently in several families, and in total was present on 11 of 22 disease chromosomes segregating in our families.

Homozygous missense variant in the human CNGA3 channel causes cone-rod dystrophy

“…[37][38][39] The CNGA3 and CNGB3 subunits are structurally similar, being composed of six transmembrane domains (S1-S6), a pore-forming region, a cyclic nucleotide-binding domain and a C-linker region (Figure 4a). While CNGA3 alone is sufficient to form functional CNG channels in heterologous expression systems, CNGB3 requires co-expression of the CNGA3 subunit.…”

Clinical and genetic investigation of a large Tunisian family with complete achromatopsia: identification of a new nonsense mutation in GNAT2 gene

“…Two genes, CNGA3 and CNGB3, which are more frequently associated to achromatopsia, 7 encode the alpha and beta subunits of cyclic guanosine monophosphate-gated cation channel in cone cells, respectively. 8,9 This channel is involved in cone membrane hyperpolarization during visual transduction. The GNAT2 gene encoding the alpha subunit of cone transducin G protein has been reported as the third most frequently affected gene, responsible for 2% of achromatopsia cases.…”

Endoplasmic Reticulum Stress-associated Cone Photoreceptor Degeneration in Cyclic Nucleotide-gated Channel Deficiency

“…Naturally occurring mutations in genes encoding CNGA3 and CNGB3 are highly associated with human cone diseases, including achromatopsia, progressive cone dystrophy, and early-onset macular degeneration (7)(8)(9). Indeed, Ͼ70 disease-associated mutations have been identified in CNGA3 and CNGB3 (8,9), and these mutations account for Ͼ70% of achromatopsia patients (7,8).…”

“…Indeed, Ͼ70 disease-associated mutations have been identified in CNGA3 and CNGB3 (8,9), and these mutations account for Ͼ70% of achromatopsia patients (7,8). Achromatopsia is a devastating hereditary visual disorder, characterized by deficient cone-mediated electroretinographic (ERG) responses, color blindness, visual acuity loss, pendular nystagmus, extreme light sensitivity, and daytime blindness.…”