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Impaired cone function and cone degeneration resulting from CNGB3 deficiency: down-regulation of CNGA3 biosynthesis as a potential mechanism.

Human molecular genetics | Dec 15, 2009

http://www.ncbi.nlm.nih.gov/pubmed/19767295

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.

Pubmed ID: 19767295 RIS Download

Mesh terms: Animals | Cyclic Nucleotide-Gated Cation Channels | Down-Regulation | Humans | Mice | Mice, Knockout | Mutation | Nerve Degeneration | Protein Biosynthesis | Retinal Cone Photoreceptor Cells | Vision, Low

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Associated grants

  • Agency: NEI NIH HHS, Id: EY00667
  • Agency: NEI NIH HHS, Id: EY007361
  • Agency: NCRR NIH HHS, Id: P20 RR017703
  • Agency: NCRR NIH HHS, Id: P20 RR017703
  • Agency: NCRR NIH HHS, Id: P20 RR017703-057340
  • Agency: NCRR NIH HHS, Id: P20 RR017703-067521
  • Agency: NCRR NIH HHS, Id: P20 RR017703-076670
  • Agency: NCRR NIH HHS, Id: P20 RR017703-086152
  • Agency: NEI NIH HHS, Id: P30 EY12190
  • Agency: NEI NIH HHS, Id: R01 EY007361

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