Molecular Defects of the Cone CNG Channel Mutations

Principal Investigator

Project Summary

Cone vision mediated by the photoreceptor cyclic nucleotide-gated (CNG) channel activation is essential for the central and color vision and vision acuity. The proper channel structure is essential for the channel function. Indeed, over 60 mutations in genes encoding the channel proteins have been linked to progressive cone dystrophy, macular degeneration, and various forms of color blindness in humans. Among these mutations, the R277C, R283W, R436W, and F547L substitution account for 42% of all detected mutant CNG A3 gene. We hypothesize that the mutations in the channel protein interfere with the proper channel structure, which in turn hampers the channel function. It is overt that elucidating the pathogenesis of mutation is essential for development of the therapeutic strategies. Thus, the main goal of this proposal is to establish the molecular basis of the channel dysfunction caused by the mutations. The first specific aim is to explore the channel structural defects in the R277C, R283W, R436W, and F547L mutants and the second specific aim is to determine the functional deficiency of the mutant channels. The long-term goal of this study is to develop the therapeutic strategies for cone dystrophy, color blindness, and macular degeneration related to the cone CNG channel mutations.

Publications

Ding, X.Q., Fitzgerald, J.B., Malykhina, A.P., and Al-Ubaidi, M.R. (2008) Functional expression of cone cyclic nucleotide-gated channel in cone photoreceptor-derived 661W cells. Adv Exp Med Biol. 613:327-334.

Matveev AV, Quiambao AB, Browning Fitzgerald J, Ding XQ. Native cone photoreceptor cyclic nucleotide-gated channel is a heterotetrameric complex comprising both CNGA3 and CNGB3: a study using the cone-dominant retina of Nrl -/- mice. J Neurochem. 2008 Sep;106(5):2042-55. Epub 2008 Jul 4.

Ding XQ, Fitzgerald JB, Matveev AV, McClellan ME, Elliott MH. Functional activity of photoreceptor cyclic nucleotide-gated channels is dependent on the integrity of cholesterol- and sphingolipid-enriched membrane domains. Biochemistry. 2008 Mar 25;47(12):3677-87. Epub 2008 Feb 28. PubMed Icon Google Scholar Icon

Ding XQ, Fitzgerald JB, Quiambao AB, Harry CS, Malykhina AP. Molecular Pathogenesis of Achromatopsia Associated with Mutations in the Cone Cyclic Nucleotide-Gated Channel CNGA3 Subunit. Adv Exp Med Biol. 2010;664:245-53.

Ding XQ, Harry CS, Umino Y, Matveev AV, Fliesler SJ, Barlow RB. Impaired cone function and cone degeneration resulting from CNGB3 deficiency: down-regulation of CNGA3 biosynthesis as a potential mechanism. Hum Mol Genet. 2009 Dec 15;18(24):4770-80. Epub 2009 Sep 17.

Matveev AV, Fitzgerald JB, Xu J, Malykhina AP, Rodgers KK, Ding XQ. The disease-causing mutations in the carboxyl terminus of the cone cyclic nucleotide-gated channel CNGA3 subunit alter the local secondary structure and interfere with the channel active conformational change. Biochemistry. 2010 Mar 2;49(8):1628-39. PubMed Icon Google Scholar Icon
 

First published on: June 11, 2008

Last modified on: February 25, 2024