Retinitis pigmentosa: Unfolding its mystery
Retinitis pigmentosa: Unfolding its mystery
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DOI：
10.1073/pnas.93.10.4526
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发表时间：
1996-05-14
影响因子：
11.1
通讯作者：
Berson, EL
中科院分区：
文献类型：
--
作者：
Berson, EL
图2(上图)正常视素在具有七个跨膜的杆状外段视盘膜中的模型。细分市场。图中第三跨膜区段的Cys-110与第二个盘内环的Cys-187之间的半胱氨酸二硫键的位置。(下图)正常视紫红质分子在三维折叠形成一个口袋以容纳维生素A来源的发色团(11顺式视网膜)，该发色团共价连接到Lys-296上，在第七跨膜区段用“K”表示。2.版权所有，1993年，视觉和眼科研究协会，马里兰州贝塞斯达))Khorana和他的同事在含有合成P23H突变基因的培养的COS细胞中发现了正确折叠和错误折叠的视蛋白混合物，这增加了具有该突变的杆状光感受器包含不同比例的折叠和错误折叠视蛋白的可能性。这还有待转基因动物模型的证实。不同数量的错误折叠视蛋白可能会导致在具有P23H突变的同龄患者中看到的不同数量的视杆故障(见图1)。Khorana和他的同事观察到，错误折叠的视蛋白在体外从11顺式视网膜异常分离，这可能与临床上发现的P23H突变患者以及T17M或T58R突变患者的视杆暗适应延迟率有关(32)。换句话说，有错误折叠的视蛋白的异常视杆可能不会结合或保持11顺式视网膜，因此具有这些突变的患者的暗适应速度比正常患者慢。与11-顺式视网膜结合的缺陷预计会导致视蛋白的不稳定和随之而来的外节视盘结构的丧失，这已在维生素A营养缺乏中观察到(33)。人类视网膜色素变性的分子遗传学研究揭示了导致疾病的视紫红质基因的广泛突变；这项研究反过来表明
FIG. 2.(Upper) Model of normal opsin in a rod outer segment disc membrane with seven transmembrane. segments. Site of cysteine disulfide bond between Cys-110 in the third transmembrane segment and Cys-187 in the second intradiscal loop is illustrated.(Lower) Representation of a normal rhodopsin molecule folded in three dimensions to form a pocket to hold the vitamin A-derived chro-mophore (11-cis-retinal), which is covalently attached to Lys-296, designated by" K" in the seventh transmembrane segment.(Modified from ref. 2. Copyright 1993, Association for Research in Vision and Ophthalmology, Bethesda, MD.)The finding by Khorana and coworkers of mixtures of correctly folded and misfolded opsins in cultured COS cells containing the synthetic P23H mutant gene raises the possibility that rod photoreceptors with this mutation contain different ratios of folded and misfolded opsins. This awaits confirmation in transgenic animal models. Varying amounts of misfolded opsin perhaps could lead to the variable amount of rod malfunction seen among patients of comparable age with the P23H mutation (see Fig. 1). The observation by Khorana and coworkers that misfolded opsins abnormally dissociate from 11-cis-retinal in vitro may have its clinical correlate in the delayed rates of rod dark adaptation that have been found in patients with the P23H mutation as well as patients with the T17M or T58R mutations (32). Stated in another way, abnormal rods with misfolded opsins may not bind or hold 11-cis-retinal so that patients with these mutations have slower than normal rates of dark adap-tation. A defect in binding to 11-cis-retinal would be expected to contribute to instability of opsin and consequent loss of outer segmentdisc structure, which has been observed in vitamin A nutritional deficiency (33). Molecular genetics studies of human retinitis pigmentosa have revealed a wide spectrum of mutations in the rhodopsin gene that result in disease; this research, inturn, indicates that