Blue Cone Monochromatism with Foveal Hypoplasia Caused by the Concomitant Effect of Variants in OPN1LW/OPN1MW and GPR143 Genes

Abstract

Blue cone monochromatism (BCM) is an X-linked recessive cone dysfunction disorder caused by mutations in the OPN1LW/OPN1MW gene cluster, encoding long (L)- and middle (M)-wavelength-sensitive cone opsins. Here, we report on the unusual clinical presentation of BCM caused by a novel mutation in the OPN1LW gene in a young man. We describe in detail the phenotype of the proband, and the subclinical morpho-functional anomalies shown by his carrier mother. At a clinical level, the extensive functional evaluation demonstrated in the proband the M/L cone affection and the sparing of S-cone function, distinctive findings of BCM. Interestingly, spectral-domain optical coherence tomography showed the presence of foveal hypoplasia with focal irregularities of the ellipsoid layer in the foveal area, reported to be associated with some cases of cone-rod dystrophy and achromatopsia. At a molecular level, we identified the novel mutation c.427T > C p.(Ser143Pro) in the OPN1LW gene and the common missense mutation c.607T > C (p.Cys203Arg) in the OPN1MW gene. In addition, we discovered the c.768-2_769delAGTT splicing variant in the GPR143 gene. To our knowledge, this is the first case of foveal hypoplasia in a BCM patient and of mild clinical affection in a female carrier caused by the concomitant effect of variants in OPN1LW/OPN1MW and GPR143 genes, thus as the result of the simultaneous action of two independent genetic defects.

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).…”

“…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.…”

Genetics of Inherited Retinal Diseases in Understudied Ethnic Groups in Italian Hospitals

“…Genetic testing was performed at MAGI’s laboratories (MAGI’s Lab s.r.l., Rovereto, TN, Italy, and MAGI Euregio s.c.s., Bolzano, Italy) and at the Genetic Unit of the Bambino Gesù children’s hospital. All protocols and their technical aspects have been published elsewhere ( Marceddu et al, 2019 ; Iarossi et al, 2021 ).…”

Ocular findings and genomics of X-linked recessive disorders: A review

“…Blue cone monochromacy [BCM] (OMIM # 303700) is a rare, X-linked congenital stationary cone dysfunction syndrome caused by mutations in either the OPN1LW (OMIM # 300822) or OPN1MW (OMIM # 300821) gene(s). [ 27 28 ]…”

“…[ 29 30 31 ] Affected individuals with BCM reported color vision impairment, nystagmus, photophobia, night vision difficulty and low vision since early childhood. [ 27 ] Myopic pattern with relative pale optic disk, regular vessel caliber and mild RPE mottling were revealed in fundus examination. Absence of foveal depression, thickening of the deep choroidal vessels, ellipsoid layer thinning in the central fovea and fragmentation of the corresponding external limiting membrane were reported in SD-OCT.[ 27 ] Absence of functional long wavelength–sensitive and medium wavelength–sensitive retinal cones is a characteristic feature.…”