title: Impaired cone function and cone degeneration resulting from CNGB3 deficiency: down-regulation of CNGA3 biosynthesis as a potential mechanism.
abstract: The cone cyclic nucleotide-gated (CNG) channel is essential for central and color vision and visual acuity. This channel is composed of two structurally related subunits, CNGA3 and CNGB3; CNGA3 is the ion-conducting subunit, whereas CNGB3 is a modulatory subunit. Mutations in both subunits are associated with achromatopsia and progressive cone dystrophy, with mutations in CNGB3 alone accounting for 50% of all known cases of achromatopsia. However, the molecular mechanisms underlying cone diseases that result from CNGB3 deficiency are unknown. This study investigated the role of CNGB3 in cones, using CNGB3(-/-) mice. Cone dysfunction was apparent at the earliest time point examined (post-natal day 30) in CNGB3(-/-) mice. When compared with wild-type (WT) controls: photopic electroretingraphic (ERG) responses were decreased by approximately 75%, whereas scotopic ERG responses were unchanged; visual acuity was decreased by approximately 20%, whereas contrast sensitivity was unchanged; cone density was reduced by approximately 40%; photoreceptor apoptosis was detected; and outer segment disorganization was observed in some cones. Notably, CNGA3 protein and mRNA levels were significantly decreased in CNGB3(-/-) mice; in contrast, mRNA levels of S-opsin, Gnat2 and Pde6c were unchanged, relative to WT mice. Hence, we show that loss of CNGB3 reduces biosynthesis of CNGA3 and impairs cone CNG channel function. We suggest that down-regulation of CNGA3 contributes to the pathogenic mechanism by which CNGB3 mutations lead to human cone disease.
authors.affiliation: Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. xi-qin-ding@ouhsc.edu
authors.forename: Xi-Qin
authors.initials: XQ
authors.lastname: Ding
authors.forename: Cynthia S
authors.initials: CS
authors.lastname: Harry
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Umino
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Matveev
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Fliesler
authors.forename: Robert B
authors.initials: RB
authors.lastname: Barlow
mesh_terms: D000818:Animals; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000172:deficiency* / Q000235:genetics; D015536:Down-Regulation; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009410:Nerve Degeneration / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014176:Protein Biosynthesis / Q000235:genetics; D017949:Retinal Cone Photoreceptor Cells / Q000378:metabolism* / Q000473:pathology; D015354:Vision, Low / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: C532622:CNGB3 protein, mouse; D054815:Cyclic Nucleotide-Gated Cation Channels