Disease mechanisms of X‐linked cone dystrophy caused by missense mutations in the red and green cone opsins

Abstract

This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmerc ial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cryo-EM structures of human cone visual pigments

“…In this study, we collected some mutations associated with color vision deficiencies (Figure 6 and Figure S8). The mutations identified within the LWS-opsin are K82 ICL1 E, N94 2.45 K, V120 ECL1 M, S143 3.42 P, W177 4.50 R, C203 ECL2 R, P231 5.50 L, R247 5.66 X, P307 7.38 L, R330 8.51 Q, and G338 8.59 E(Nathans et al, 1993; Ueyama et al, 2002; Carroll et al, 2004; Ueyama et al, 2004; Mizrahi-Meissonnier et al, 2010; Cai et al, 2019; Iarossi et al, 2021; Zhu et al, 2021) (Figures 6A and S8A). It is noteworthy that the C203 ECL2 R mutation disrupts the disulfide bond linkage between C203 ECL2 and C126 3.25 , which is also observed in MWS-opsin (Figure 6B).…”

“…For MWS-opsin, in accordance with LWS-opsin, the mutation C203 ECL2 R disrupts the disulfide bond between C203 ECL2 and C126 3.25 (Figure 6B). Moreover, N94 2.45 K, W177 4.50 R, P307 7.38 L, R330 8.51 Q, and G338 8.59 E mutations can also lead to color vision deficiency(Ueyama et al, 2002; Zhu et al, 2021) (Figures 6B and S8B). The MWS-opsin missense mutation P187 4.60 S has been identified in subjects with color-vision deficiency(Neitz et al, 2004), and P187 ECL2 is conserved among vertebrate visual pigments (Figure S1).…”

“…Previous studies have reported that missense mutations in cone opsins associated with color vision deficiencies, however, the specific mechanisms remain unclear. (Weitz et al, 1992; Nathans et al, 1993; Ueyama et al, 2002; Carroll et al, 2004; Ueyama et al, 2004; Neitz et al, 2004; Mizrahi-Meissonnier et al, 2010; Cai et al, 2019; Neitz et al, 2020; Iarossi et al, 2021; Zhu et al, 2021). Our findings also provide some molecular insights from the structural perspective to color vision deficiencies.…”

“…As color discrimination predominantly depends on opsins in cones, elucidating the structure of human cone opsins contributes to a better understanding of vision-related diseases. For instance, mutations in cone opsins may be associated with certain hereditary visual impairments(Neitz et al, 2020; Zhu et al, 2021), and structural studies will assist in revealing how these mutations affect visual function.…”

Expression of red/green-cone opsin mutants K82E, P187S, M273K result in unique pathobiological perturbations to cone structure and function

“…Though very rare, point mutations have been identified in subjects with congenital BCM or color-vision deficiency. In a previous study, we used an AAV-based gene delivery approach to investigate the in vivo expression pattern and pathobiology of five cone opsin missense mutations (N94K, W177R, P307L, R330Q, and G338E) after expression in M-opsin knockout ( Opn1mw −/− ) mice ( Zhu et al, 2021 ). In this study, we characterize the disease mechanisms of three additional cone opsin missense mutants that have been shown to cause color-vison deficiency or BCM ( Neitz et al, 2004 ; Katagiri et al, 2018 ; Cai et al, 2019 ).…”