Blindness Caused by Deficiency in AE3 Chloride/Bicarbonate Exchanger

Abstract

BackgroundVision is initiated by phototransduction in the outer retina by photoreceptors, whose high metabolic rate generates large CO2 loads. Inner retina cells then process the visual signal and CO2. The anion exchanger 3 gene (AE3/Slc4a3) encodes full-length AE3 (AE3fl) and cardiac AE3 (AE3c) isoforms, catalyzing plasma membrane Cl−/HCO3 − exchange in Müller (AE3fl) and horizontal (AE3c) cells. AE3 thus maintains acid-balance by removing photoreceptor-generated CO2 waste.Methodology/Principal FindingsWe report that Slc4a3−/− null mice have inner retina defects (electroretinogram b-wave reduction, optic nerve and retinal vessel anomalies). These pathologic features are common to most human vitreoretinal degenerations. Immunobloting analysis revealed that Na+/HCO3 − co-transporter (NBC1), and carbonic anhydrase II and CAXIV, protein expression were elevated in Slc4a3 −/− mouse retinas, suggesting compensation for loss of AE3. TUNEL staining showed increased numbers of apoptotic nuclei from 4–6 months of age, in Slc4a3 −/− mice, indicating late onset photoreceptor death.Conclusions/SignificanceIdentification of Slc4a3 as underlying a previously unrecognized cause of blindness suggests this gene as a new candidate for a subset of hereditary vitreoretinal retinal degeneration.

Bicarbonate homeostasis in excitable tissues: role of AE3 Cl−/HCO3− exchanger and carbonic anhydrase XIV interaction

“…The ability to maintain acid-base balance in the ae3 Ϫ/Ϫ inner retina was dramatically compromised and was not fully compensated by other pH regulatory proteins. Anatomical pathological features and late onset cell death accompanied functional defects in ae3 Ϫ/Ϫ mice retinas (1).…”

Altered visual function in monocarboxylate transporter 3 (Slc16a8) knockout mice

“…pH homeostasis in the outer retina is maintained by the coordinated activities of electrogenic Na ϩ /HCO 3 Ϫ cotransporters, Na ϩ /H ϩ exchangers, Na ϩ /HCO 3 Ϫ exchangers, and carbonic anhydrases (CA). Mutations in genes that contribute to acid-base regulation in the retina are known to cause ocular phenotypes with varying degrees of severity (2,3,7,17,29). CA XIV is an integral membrane protein with an extracellular catalytic domain that is expressed in the apical processes of both Müller and RPE cells.…”

Molecular physiology and genetics of Na+-independent SLC4 anion exchangers

“…Distinct Ae3 isoforms are also expressed in Muller cells and horizontal neurons of the retina (Kobayashi et al, 1994). One line of Ae3 -/-mice exhibits late onset retinal degeneration and progressive blindness at 4-6 months of age, accompanied by upregulation of NBCe1/SLC4A4, CAII and CAIV (Alvarez et al, 2007a). Retinal Ae3 deficiency might alter chloride equilibrium potential to decrease GABA-or glycine-mediated inhibitory input, as postulated for the Ae3 -/-brain.…”