Proposed therapy, developed in a Pcdh15-deficient mouse, for progressive loss of vision in human Usher syndrome.
Proposed therapy, developed in a Pcdh15-deficient mouse, for progressive loss of vision in human Usher syndrome.
复制标题
在pcdh15缺陷小鼠中开发的治疗人类Usher综合征进行性视力丧失的拟议疗法。
DOI：
10.7554/elife.67361
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发表时间：
2021-11-09
期刊：
影响因子：
7.7
通讯作者：
Ahmed ZM
中科院分区：
文献类型：
--
作者：
Sethna S;Zein WM;Riaz S;Giese AP;Schultz JM;Duncan T;Hufnagel RB;Brewer CC;Griffith AJ;Redmond TM;Riazuddin S;Friedman TB;Ahmed ZM
I 型亚瑟综合征 (USH1) 的特点是耳聋、前庭反射消失和进行性视网膜变性。 PCDH15 (USH1F) 的蛋白质截短 p.Arg245* 创始人变体在德系犹太人中的携带频率约为 2%，约占 USH1 病例的 60%。在这里，13 个 USH1F 个体的纵向表型分析显示进行性视网膜变性，导致到 60 岁时严重视力丧失并伴有黄斑萎缩。一半受影响的人在 50 多岁时就已经失明。小鼠 Pcdh15R250X 变体相当于人类 p.Arg245*。纯合 Pcdh15R250X 小鼠还具有视觉缺陷和光转导级联蛋白、抑制蛋白和转导蛋白的异常光依赖性易位。 Pcdh15R250X 小鼠中视网膜色素上皮 (RPE) 特异性视黄醇循环蛋白 RPE65 和 CRALBP 也减少，表明原钙粘蛋白-15 在光感受器和 RPE 中具有双重作用。外源性 9-顺式视网膜改善了 Pcdh15R250X 小鼠的 ERG 振幅，这为 FDA 批准的类维生素A用于保护 USH1F 患者视力的临床试验奠定了基础。
Usher syndrome type I (USH1) is characterized by deafness, vestibular areflexia, and progressive retinal degeneration. The protein-truncating p.Arg245* founder variant of PCDH15 (USH1F) has an ~2% carrier frequency amongst Ashkenazi Jews accounts for ~60% of their USH1 cases. Here, longitudinal phenotyping in 13 USH1F individuals revealed progressive retinal degeneration, leading to severe vision loss with macular atrophy by the sixth decade. Half of the affected individuals were legally blind by their mid-50s. The mouse Pcdh15R250X variant is equivalent to human p.Arg245*. Homozygous Pcdh15R250X mice also have visual deficits and aberrant light-dependent translocation of the phototransduction cascade proteins, arrestin, and transducin. Retinal pigment epithelium (RPE)-specific retinoid cycle proteins, RPE65 and CRALBP, were also reduced in Pcdh15R250X mice, indicating a dual role for protocadherin-15 in photoreceptors and RPE. Exogenous 9-cis retinal improved ERG amplitudes in Pcdh15R250X mice, suggesting a basis for a clinical trial of FDA-approved retinoids to preserve vision in USH1F patients.