Purchase this article with an account.
Gao-Hui Zhou, Lue Xiang, Xiu-Feng Huang, Xin-Lan Lei, Ji-Neng Lv, Kun-Chao Wu, Xiao-Yun Wang, Zi-Bing Jin; Mutation in ATP1A3 is associated with dominant cone-rod dystrophy. Invest. Ophthalmol. Vis. Sci. 2018;59(9):2323.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Na+, K+-ATPase (sodium/potassium pump) is substantial to keep the ion balance for the cell. Genetic study have revealed that mutations in ATP1A3, the gene encoding the α3 subunit of Na+, K+-ATPase, cause multiple neurological diseases, including Cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome (OMIM 601338) [2-4]. However, the relationship between the mutations in this gene and retinal diseases have not been clarified. Due to the high expression level of Atp1a3 in mouse retina and the genetic evidence from the dominant cone-rod dystrophy patients, we generated an Atp1a3 knockin mice to understand the function of this gene in photoreceptor cells in vivo and in vitro.
Atp1a3 knockin mice were generated using ESC-based gene targeting technology. Fundus photography, spectral-domain optical coherence tomography (SD-OCT), and Ganzfeld electroretinography (ERG) were utilized to detect retinal function and structure in vivo. The thicknesses of every layers and morphology of different cells in retina were analyzed by immunostaining. The Seahorse Extracellular Flux Analyzer were used to test oxygen consumption rate (OCR), which can reflect mitochondrial respiration and reserve capacity.
Using exome sequencing, we identified a dominant mutation in the ATP1A3 gene in a retinal degeneration family comprising four patients. These patients showed relative normal fundus photography, whereas macular fovea were thinner revealed by SD-OCT. ERG responses were extinguished. As similar as the observation in the patients, no significant structural and morphological abnormalities were detected in Atp1a3 mutant mouse retinas. Both a-wave and b-wave amplitudes of photopic ERGs decreased much more significant than Scotopic ones. The cells overexpressing mutant ATP1A3 protein had reduced OCR than the control group (p < 0.05, 1-way ANOVA and Dunnett’s post hoc test).
These results suggest that ATP1A3 is a novel gene associated with dominant cone-rod dystrophy. Mechanistic study indicated that the mutation (exon13, c.1772A>T, p.D591V) in this gene may involves mitochondrial dysfunction.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
This PDF is available to Subscribers Only