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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Recessive NRL mutations in patients with clumped pigmentary retinal degeneration and relative preservation of blue cone function.
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Recessive NRL mutations in patients with clumped pigmentary retinal degeneration and relative preservation of blue cone function.

机译：聚集性视网膜色素变性和蓝锥功能相对保留的患者的隐性NRL突变。

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摘要

Mice lacking the transcription factor Nrl have no rod photoreceptors and an increased number of short-wavelength-sensitive cones. Missense mutations in NRL are associated with autosomal dominant retinitis pigmentosa; however, the phenotype associated with the loss of NRL function in humans has not been reported. We identified two siblings who carried two allelic mutations: a predicted null allele (L75fs) and a missense mutation (L160P) altering a highly conserved residue in the domain involved in DNA-binding-site recognition. In vitro luciferase reporter assays demonstrated that the NRL-L160P mutant had severely reduced transcriptional activity compared with the WT NRL protein, consistent with a severe loss of function. The affected patients had night blindness since early childhood, consistent with a severe reduction in rod function. Color vision was normal, suggesting the presence of all cone color types; nevertheless, a comparison of central visual fields evaluated with white-on-white and blue-on-yellow light stimuli was consistent with a relatively enhanced function of short-wavelength-sensitive cones in the macula. The fundi had signs of retinal degeneration (such as vascular attenuation) and clusters of large, clumped, pigment deposits in the peripheral fundus at the level of the retinal pigment epithelium (clumped pigmentary retinal degeneration). Our report presents an unusual clinical phenotype in humans with loss-of-function mutations in NRL.
机译：缺乏转录因子Nrl的小鼠没有杆状感光体，并且短波长敏感视锥细胞的数量增加。 NRL的错义突变与常染色体显性遗传性视网膜色素变性有关。然而，尚未报道与人类NRL功能丧失相关的表型。我们确定了携带两个等位基因突变的两个兄弟姐妹：预测的无效等位基因（L75fs）和一个错义突变（L160P），它们改变了涉及DNA结合位点识别的域中高度保守的残基。体外荧光素酶报告基因测定表明，与野生型NRL蛋白相比，NRL-L160P突变体的转录活性大大降低，这与功能的严重丧失相一致。患病的儿童自幼年以来就患有夜盲症，这与杆功能严重降低相一致。色觉正常，表明存在所有圆锥颜色。然而，用白光和蓝光黄光刺激评估的中心视野的比较与黄斑中短波长敏感视锥细胞相对增强的功能相一致。眼底有视网膜变性的迹象（例如血管衰减），并且在视网膜色素上皮水平的周围眼底周围聚集着大量团块状色素沉积物（团块状色素性视网膜变性）。我们的报告提出了具有NRL功能丧失突变的人类中异常的临床表型。

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