State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China.
Ophthalmic Molecular Genetics Section, Ophthalmic Genetics and Visual Function Branch, National Eye Institute, Rockville, Maryland, United States.
Invest Ophthalmol Vis Sci. 2023 Apr 3;64(4):29. doi: 10.1167/iovs.64.4.29.
Specific haplotypes (LVAVA, LIVVA, and LIAVA) formed by five polymorphisms (p.L153M, p.V171I, p.A174V, p.I178V, and p.S180A in exon 3 of OPN1LW) that cause partial or complete exon skipping have been reported as unique genetic causes of high myopia with or without colorblindness. This study aimed to identify the contribution of OPN1LW to early-onset high myopia (eoHM) and the molecular basis underlying eoHM with or without colorblindness.
Comparative analysis of exome sequencing data was conducted for 1226 families with eoHM and 9304 families with other eye conditions. OPN1LW variants detected by targeted or whole exome sequencing were confirmed by long-range amplification and Sanger sequencing, together with segregation analysis. The clinical data were thoroughly analyzed.
Unique haplotypes and truncation variants in OPN1LW were detected exclusively in 68 of 1226 families with eoHM but in none of the 9304 families with other visual diseases (P = 1.63 × 10-63). Four classes of variants were identified: haplotypes causing partial splicing defects in OPN1LW (LVAVA or LIVVA in 31 families), LVAVA in OPN1LW-OPN1MW hybrid gene (in 3 families), LIAVA in OPN1LW (in 29 families), and truncations in OPN1LW (in 5 families). The first class causes partial loss of red photopigments, whereas the latter three result in complete loss of red photopigments. This is different from the replacement of red with green owing to unequal re-arrangement causing red-green colorblindness alone. Of the 68 families, 42 affected male patients (31 families) with the first class of variants (LVAVA or LIVVA in OPN1LW) had eoHM alone, whereas 37 male patients with the latter 3 classes had eoHM with protanopia. Adaptive optics retinal imaging demonstrated reduced cone regularity and density in men with eoHM caused by OPN1LW variants compared to those patients with eoHM and without OPN1LW variants.
Based on the 68 families with unique variants in OPN1LW, our study provides firm evidence that the two different phenotypes (eoHM with or without colorblindness) are caused by two different classes of variants (partial splicing-effect haplotypes or complete splicing-effect haplotypes/truncation variants, respectively). The contribution of OPN1LW to eoHM (isolated and syndromic) was characterized by OPN1LW variants found in 5.5% (68/1226) of the eoHM families, making it the second most common cause of monogenic eoHM alone (2.4%) and a frequent cause of syndromic monogenic eoHM with colorblindness. Such haplotypes, in which each individual variant alone is considered a benign polymorphism, are potential candidates for other hereditary diseases with causes of missing genetic defects.
由五个多态性（OPN1LW 外显子 3 中的 p.L153M、p.V171I、p.A174V、p.I178V 和 p.S180A）形成的特定单倍型（LVAVA、LIVVA 和 LIAVA）导致部分或完全外显子跳跃，已被报道为导致高度近视（HM）伴或不伴色盲的独特遗传原因。本研究旨在确定 OPN1LW 对早发性 HM（eoHM）的贡献以及 eoHM 伴或不伴色盲的分子基础。
对 1226 个 eoHM 家系和 9304 个其他眼部疾病家系进行外显子组测序数据的比较分析。通过靶向或全外显子组测序检测到的 OPN1LW 变异，通过长距离扩增和 Sanger 测序进行验证，并进行遗传分析。对临床数据进行了深入分析。
在 1226 个 eoHM 家系中，仅在 68 个家系中检测到 OPN1LW 中独特的单倍型和截断变异，而在 9304 个其他视觉疾病家系中则未检测到（P=1.63×10-63）。鉴定出 4 类变异：导致 OPN1LW 部分剪接缺陷的单倍型（31 个家系中的 LVAVA 或 LIVVA）、OPN1LW-OPN1MW 杂合基因中的 LVAVA（3 个家系）、OPN1LW 中的 LIAVA（29 个家系）和 OPN1LW 中的截断（5 个家系）。第一类导致部分红色视蛋白缺失，而后三类导致红色视蛋白完全缺失。这与由于不等重排导致红色被绿色取代而导致的色盲不同。在 68 个家系中，42 名受影响的男性患者（31 个家系）携带第一类变异（OPN1LW 中的 LVAVA 或 LIVVA），仅患有 eoHM，而 37 名携带后三类变异的男性患者患有 eoHM 伴红绿色盲。与不携带 OPN1LW 变异的 eoHM 患者相比，适应性光学视网膜成像显示 OPN1LW 变异所致男性 eoHM 患者的锥体规则性和密度降低。
基于 68 个具有独特 OPN1LW 变异的家系，本研究提供了确凿的证据，表明两种不同的表型（eoHM 伴或不伴色盲）由两种不同类别的变异（部分剪接效应单倍型或完全剪接效应单倍型/截断变异）引起。OPN1LW 对 eoHM（孤立型和综合征型）的贡献由在 5.5%（68/1226）eoHM 家系中发现的 OPN1LW 变异所决定，使其成为第二大常见的单纯性单基因 eoHM 原因（2.4%），也是常染色体显性遗传单基因 eoHM 伴色盲的常见原因。这些单倍型中，每个单独的变异都被认为是良性多态性，可能是其他具有缺失遗传缺陷的遗传疾病的候选者。
