Disease relevance of CNGB3

• Recently, mutations in the gene encoding the CNGB3 subunit have been linked to achromatopsia in humans [1].
• Based on our findings, CNGB3 should be considered as a candidate gene to be evaluated in patients with forms of cone dysfunction, including macular degeneration [2].

High impact information on CNGB3

• Here we narrow the achromatopsia locus to 1.4 cM and show that Pingelapese achromatopsia segregates with a missense mutation at a highly conserved site in CNGB3, a new gene that encodes the beta-subunit of the cone cyclic nucleotide-gated cation channel [3].
• Two independent frameshift deletions establish that achromatopsia is the null phenotype of CNGB3 [3].
• Cone photoreceptor cyclic nucleotide-gated (CNG) channels are thought to be tetrameric assemblies of CNGB3 (B3) and CNGA3 (A3) subunits [4].
• Canine CNGB3 mutations establish cone degeneration as orthologous to the human achromatopsia locus ACHM3 [5].
• A deletion removing all exons of canine CNGB3 was identified in cd-affected Alaskan Malamute-derived dogs [5].

Biological context of CNGB3

• The derived CNGB3 mutation spectrum comprises 28 different mutations including 12 nonsense mutations, eight insertions and/or deletions, five putative splice site mutations, and three missense mutations [6].
• This indicates that the CNGB3/ACHM3 locus on chromosome 8q21 is the major locus for achromatopsia in patients of European origin or descent [6].
• The human CNGB3 gene consists of 18 exons distributed over approximately 200 kb of genomic sequence [7].
• PCR/RFLP analysis and DNA sequencing was applied for mutation screening of CNGA3 and CNGB3 [8].
• All three individuals with this progressive phenotype were found to be compound heterozygotes for the 1148delC (Thr383fs) frameshift mutation and a novel Arg403Gln missense mutation in CNGB3 [9].

Anatomical context of CNGB3

• Achromatopsia-associated mutation in the human cone photoreceptor cyclic nucleotide-gated channel CNGB3 subunit alters the ligand sensitivity and pore properties of heteromeric channels [1].
• Co-expression in Xenopus oocytes of human CNGA3 (hCNGA3) subunits with hCNGB3 subunits containing an achromatopsia-associated mutation in the S6 transmembrane domain (S435F) generated functional heteromeric channels that exhibited an increase in apparent affinity for both cAMP and cGMP compared with wild type heteromeric channels [1].

Associations of CNGB3 with chemical compounds

• Thus, both NH2- and COOH-terminal CaM-binding sites in CNGB3 are functionally important for regulation of recombinant cone CNG channels [10].
• However, the tyrosine residue in CNGB3 (Tyr545) that is equivalent to the critical tyrosine residues in rod and olfactory CNG channel subunits does not participate in cone channel regulation [11].
• Furthermore, the changes in ligand sensitivity of CNGA3 + CNGB3 channels were prevented by inhibition of phosphatidylinositol 3-kinase (PI3-kinase) using wortmannin or 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride (LY294002), which suggests that phospholipid metabolism can regulate the channels [11].
• Glycerol treatment did not rescue channel function nor did coexpression with CNGB3, a subunit of native hetero-tetrameric cone channels [12].

Other interactions of CNGB3

• Cone photoreceptor cyclic nucleotide-gated (CNG) channels are thought to form by assembly of two different subunit types, CNGA3 and CNGB3 [1].
• Mutations in the genes for CNGA3, CNGB3, and GNAT2 have been associated with this disorder [6].
• Functional role of hCngb3 in regulation of human cone cng channel: effect of rod monochromacy-associated mutations in hCNGB3 on channel function [13].

Analytical, diagnostic and therapeutic context of CNGB3

• Second, chemical crosslinking and co-immunoprecipitation studies using epitope-tagged monomer subunits both demonstrated the presence of two CNGB3 subunits in cone channels [4].
• Using RT-PCR and RACE, we identified and cloned the human cDNA homologue, designated CNGB3, which encodes an 809 amino acid polypeptide [7].

References