Mutations in the cellular retinaldehyde–binding protein (CRALBP, encoded by RLBP1) can lead to severe cone photoreceptor–mediated vision loss in patients. It is not known how CRALBP supports cone function or how altered CRALBP leads to cone dysfunction. Here, we determined that deletion of Rlbp1 in mice impairs the retinal visual cycle. Mice lacking CRALBP exhibited M-opsin mislocalization, M-cone loss, and impaired cone-driven visual behavior and light responses. Additionally, M-cone dark adaptation was largely suppressed in CRALBP-deficient animals. While rearing CRALBP-deficient mice in the dark prevented the deterioration of cone function, it did not rescue cone dark adaptation. Adeno-associated virus–mediated restoration of CRALBP expression specifically in Müller cells, but not retinal pigment epithelial (RPE) cells, rescued the retinal visual cycle and M-cone sensitivity in knockout mice. Our results identify Müller cell CRALBP as a key component of the retinal visual cycle and demonstrate that this pathway is important for maintaining normal cone–driven vision and accelerating cone dark adaptation.
Yunlu Xue, Susan Q. Shen, Jonathan Jui, Alan C. Rupp, Leah C. Byrne, Samer Hattar, John G. Flannery, Joseph C. Corbo, Vladimir J. Kefalov
(A) Representative in vivo cone ERG responses from control (black traces), Rlbp1–/– (red traces), and Rlbp1+/– (blue traces) mice. Test flash intensities increased from 2.27 × 10–2 cd × s/m2 (bottom traces) to 697 cd × s/m2 (top traces) in steps of approximately 0.5 log units. (B) Ensemble-averaged cone b-wave intensity-response curves for control (n = 10), Rlbp1–/– (n = 12), and Rlbp1+/– (n = 10) mice. (C) Cone b-wave intensity-response curves for control mice aged 6–7 weeks (black squares, n = 8) and 13–16 weeks (white squares, n = 10). (D) Cone b-wave intensity-response curves for Rlbp1–/– mice aged 6–7 weeks (red circles, n = 6) and 13–16 weeks (white circles, n = 6). Insets in B–D show the corresponding normalized (r/rmax) intensity-response curves. Results represent the mean ± SEM.