Abstract：
Certain combinations of common variants in exon 3 of OPN1LW and OPN1MW, the genes encoding the apo-protein of the long- and middle-wavelength sensitive cone photoreceptor visual pigments in humans, induce splicing defects and have been associated with dyschromatopsia and cone dysfunction syndromes. Here we report the identification of a novel exon 3 haplotype, G-C-G-A-T-T-G-G (referring to nucleotide variants at cDNA positions c.453, c.457, c.465, c.511, c.513, c.521, c.532, and c.538) deduced to encode a pigment with the amino acid residues L-I-V-V-A at positions p.153, p.171, p.174, p.178, and p.180, in OPN1LW or OPN1MW or both in a series of seven patients from four families with cone dysfunction. Applying minigene assays for all observed exon 3 haplotypes in the patients, we demonstrated that the novel exon 3 haplotype L-I-V-V-A induces a strong but incomplete splicing defect with 3-5% of residual correctly spliced transcripts. Minigene splicing outcomes were similar in HEK293 cells and the human retinoblastoma cell line WERI-Rb1, the latter retaining a cone photoreceptor expression profile including endogenous OPN1LW and OPN1MW gene expression. Patients carrying the novel L-I-V-V-A haplotype presented with a mild form of Blue Cone Monochromacy or Bornholm Eye Disease-like phenotype with reduced visual acuity, reduced cone electroretinography responses, red-green color vision defects, and frequently with severe myopia.
摘要：
OPN1LW和OPN1MW的外显子3中常见变体的某些组合，编码人类中长波长敏感视锥感光体视觉色素apo蛋白的基因，诱导剪接缺陷，并与色泽异常和视锥细胞功能障碍综合征有关。在这里，我们报告了一个新的外显子3单倍型的鉴定，G-C-G-A-T-T-G-G-G（指cDNA位置c.453，c.457，c.465，c.511，c.513，c.521，c.532和c.538的核苷酸变体）推导出编码在P.153，p.171，p.174，p.178和p.180位氨基酸残基L-I-V-V-A的色素，来自O对患者中所有观察到的外显子3单倍型应用小基因测定，我们证明了新的外显子3单倍型L-I-V-V-A诱导了强烈但不完全的剪接缺陷，其中3-5％的残余正确剪接转录本。在HEK293细胞和人视网膜母细胞瘤细胞系WERI-Rb1中，小基因剪接结果相似，后者保留了圆锥光感受器表达谱，包括内源性OPN1LW和OPN1MW基因表达。携带新型L-I-V-V-A单倍型的患者表现为轻度形式的蓝锥单色或博恩霍尔姆眼病样表型，视力下降，减少锥形视网膜电图反应，红绿色视觉缺陷，经常患有严重近视。
