The cone cyclic nucleotide-gated (CNG) channel is essential for central and color vision and for visual acuity. Mutations in the two channel subunits, CNGA3 and CNGB3, are associated with achromatopsia and progressive cone dystrophy. Cones degenerate in mouse models of CNGA3 and CNGB3 deficiency and in patients with achromatopsia or cone dystrophy. There are currently no curative treatments for these diseases, in part due to a lack of understanding of the mechanisms underlying the disease pathobiology. The overarching objective of this study is to understand the mechanism(s) of cone degeneration resulting from loss of CNG channel function. Specifically, we will determine whether the accumulation of cGMP in models of CNG channel deficiency causes cone degeneration. We will perform the proposed studies using the CNGA3-/-/Nrl-/- and CNGB3-/-/Nrl-/- mouse lines. Using these mouse models provides a unique opportunity to study cone degeneration in a retina that contains only cones.
Three specific aims are proposed. The first specific aim is to determine whether the accumulation of cGMP is responsible for cone degeneration in CNGA3 deficiency. We will test the ability of guanylate cyclase (GC) inhibitors to reduce cone degeneration in the channel-deficient mice. In a corroborating experiment, we will also test this hypothesis by abolishing expression of retGC-1 (retinal guanlyate cyclase) in channel deficient cones by utilizing RNAi and/or genetic methods (generation of CNGA3-/-/Nrl-/-/retGC-1-/-). The second specific aim is to determine how cones die in CNGA3 deficiency. If cGMP is responsible for cone cell death, we will examine how the accumulation of cGMP leads to cone cell death. We will investigate the role of cGMP- dependent protein kinase (PKG) in cone degeneration. We will determine whether PKG activity is higher in the CNGA3-/-/Nrl-/- retina compared to the Nrl-/- retina, and will test whether the use of PKG inhibitors/knockdown of PKG expression can ameliorate cone degeneration. Alternate mechanisms for cone degeneration will also be investigated by studying altered gene expression in channel deficient mice (compared to WT) by using microarray analysis. The third specific aim is to determine whether CNGB3 deficiency leads to an accumulation of cGMP in cones by using CNGB3-/-/Nrl-/- mice. Upon completion of the proposed study we will have a better understanding of the mechanism(s) underlying cone degeneration resulting from CNG channel deficiency. Improving the lifespan of degenerating cones is necessary for successful treatment of inherited cone diseases. The knowledge gained in this study is crucial for the development of therapeutic strategies to prevent or retard this degeneration, both in cases in which the causative gene is one of the channel proteins and in more general cases of cone dystrophy.

Public Health Relevance

Congenital achromatopsia and progressive cone dystrophy are debilitating hereditary vision disorders for which there are currently no curative treatments. Mutations in genes encoding the cone cyclic nucleotide- gated (CNG) channel subunits account for 70% of all known cases of achromatopsia. The proposed study will probe the mechanisms underlying the cone degeneration that leads to loss of vision in CNG channel- associated achromatopsia. The results will provide significant insights into both the normal cell biology of cones and the pathobiology of cone dominant inherited disease. This knowledge is essential for developing therapeutic interventions to treat cone diseases and retard or rescue vision loss.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-CB-G (90))
Program Officer
Neuhold, Lisa
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Oklahoma Health Sciences Center
Anatomy/Cell Biology
Schools of Medicine
Oklahoma City
United States
Zip Code
Yang, Fan; Ma, Hongwei; Boye, Sanford L et al. (2018) Overexpression of Type 3 Iodothyronine Deiodinase Reduces Cone Death in the Leber Congenital Amaurosis Model Mice. Adv Exp Med Biol 1074:125-131
Yang, Fan; Ma, Hongwei; Ding, Xi-Qin (2018) Thyroid Hormone Signaling in Retinal Development, Survival, and Disease. Vitam Horm 106:333-349
Ma, Hongwei; Yang, Fan; Butler, Michael R et al. (2017) Inhibition of thyroid hormone receptor locally in the retina is a therapeutic strategy for retinal degeneration. FASEB J 31:3425-3438
Butler, Michael R; Ma, Hongwei; Yang, Fan et al. (2017) Endoplasmic reticulum (ER) Ca2+-channel activity contributes to ER stress and cone death in cyclic nucleotide-gated channel deficiency. J Biol Chem 292:11189-11205
Ma, Hongwei; Ding, Xi-Qin (2016) Thyroid Hormone Signaling and Cone Photoreceptor Viability. Adv Exp Med Biol 854:613-8
Yang, Fan; Ma, Hongwei; Belcher, Joshua et al. (2016) Targeting iodothyronine deiodinases locally in the retina is a therapeutic strategy for retinal degeneration. FASEB J 30:4313-4325
Ding, Xi-Qin; Thapa, Arjun; Ma, Hongwei et al. (2016) The B3 Subunit of the Cone Cyclic Nucleotide-gated Channel Regulates the Light Responses of Cones and Contributes to the Channel Structural Flexibility. J Biol Chem 291:8721-34
Ma, Hongwei; Butler, Michael R; Thapa, Arjun et al. (2015) cGMP/Protein Kinase G Signaling Suppresses Inositol 1,4,5-Trisphosphate Receptor Phosphorylation and Promotes Endoplasmic Reticulum Stress in Photoreceptors of Cyclic Nucleotide-gated Channel-deficient Mice. J Biol Chem 290:20880-92
Boye, Sanford L; Peterson, James J; Choudhury, Shreyasi et al. (2015) Gene Therapy Fully Restores Vision to the All-Cone Nrl(-/-) Gucy2e(-/-) Mouse Model of Leber Congenital Amaurosis-1. Hum Gene Ther 26:575-92
Du, Wei; Tao, Ye; Deng, Wen-Tao et al. (2015) Vitreal delivery of AAV vectored Cnga3 restores cone function in CNGA3-/-/Nrl-/- mice, an all-cone model of CNGA3 achromatopsia. Hum Mol Genet 24:3699-707

Showing the most recent 10 out of 24 publications