PHENOTYPES OF RETINITIS PIGMENTOSA RHODOPSIN MUTATIONS

遗传性视网膜色素变性(RP)的研究进展 以及目前无法治愈的视网膜变性，最近发生在 研究发现，在美国，近25%的常染色体显性遗传(AD) 这种疾病的形式是由编码杆状病毒的基因突变引起的 视觉色素，视紫红质。由此产生的一个重要问题是 分子遗传学的发现是：分子病理学是如何导致 视杆感光细胞功能障碍和进行性视网膜变性？一个 许多不同的科学方法，从分子到 临床，已经在朝着这个问题的答案前进。 我们已经开始了对ADRP患者的研究，以了解 分子病变与临床表型的关系 代表视紫红质基因7个不同点突变的患者 通过视网膜功能的非侵入性测试进行了研究 特别是视紫红质和视杆感受器的特性 生理学。这些初步研究表明，adrp患者受到轻微影响。 不同的视紫红质基因有明显不同的模式 视觉功能障碍。此外，对于那里研究的每一种基因类型 是家族内和家族间表型表达的一致性。 一个特别有趣的发现是，某些基因类型具有 视杆适应的时间进程异常。这些初步的 结果应该扩展到更多的家系和更多的突变。 这个应用程序建议测试假设，如果疾病 通过视紫红质和视杆介导的测试来确定表达 光感受器的功能，那么每个感光器之间存在可定义的关系 ADRP视紫红质基因及其表型。我们的 具体目标是：描述视网膜功能障碍的类型 一大系列代表13种视紫红质基因的患者使用 心理物理学、电生理学和眼底反射术；检查 模式随着疾病的进展而变化；以确定 家庭内和家庭间结果的一致性；并量化 在某些基因类型中发现的杆状适应异常 模特儿。我们还将通过以下方式测试表型发现的特异性 研究ADRP患者的野生型视紫红质，并将我们的研究扩展到 更多的视紫红质基因型以及其他RP基因型 可用。 拟议研究的结果应允许制定和 生化和生理功能失调假说的检验 视紫红质ADRP患者视杆内光感受器内的事件 突变。了解每种基因的功能特性 对规划未来RP的临床研究也应该有价值， 尤其是在决定哪些视网膜机制可以和应该被监测时 在这些患者的自然历史研究和治疗试验中。

Progress in understanding retinitis pigmentosa (RP), a group of hereditary and presently incurable retinal degenerations, occurred recently with the discovery that, in the United States, nearly 25% of autosomal dominant (AD) forms of the disease result from mutations in the gene encoding the rod visual pigment, rhodopsin. An important question arising from these molecular genetic discoveries is: How does the molecular pathology lead to rod photoreceptor dysfunction and progressive retinal degeneration? A number of different scientific approaches, from the molecular to the clinical, are already proceeding toward answers to this question. We have initiated studies of ADRP patients in order to understand the relationship between the molecular lesions and the clinical phenotype. Patients representing 7 different point mutations in the rhodopsin gene were studied with non-invasive tests of retinal function that depend specifically on the properties of rhodopsin and rod photoreceptor physiology. These pilot studies showed that mildly affected ADRP patients with different rhodopsin genotypes have clearly different patterns of visual dysfunction. Furthermore, for each of the genotypes studied there was intrafamilial and interfamilial consistency of phenotypic expression. A finding of special interest was that certain genotypes had characteristic abnormalities in the time course of rod adaptation. These preliminary results should be extended to additional families and additional mutations. This application proposes to test the hypothesis that, if disease expression is determined with tests of rhodopsin and rod-mediated photoreceptor function, then there is a definable relationship between each ADRP rhodopsin genotype and the phenotype resulting therefrom. Our specific aims are: to characterize the patterns of retinal dysfunction in a large series of patients representing 13 rhodopsin genotypes using psychophysics, electrophysiology and fundus reflectometry; to examine variations in pattern with progression of the diseases; to determine intrafamilial and interfamilial consistency of findings; and to quantify rod adaptation abnormalities found in certain genotypes with mathematical modeling. We will also test the specificity of phenotypic findings by studying ADRP patients with wild-type rhodopsin and extend our studies to more rhodopsin genotypes as well as other RP genotypes as they become available. The results of the proposed studies should permit the formulation and testing of hypotheses about the dysfunctional biochemical and physiological events within the rod photoreceptors of ADRP patients with rhodopsin mutations. Knowledge of the functional characteristics of each genotype should also be of value in planning future clinical studies of RP, especially in deciding which retinal mechanisms can and should be monitored in natural history studies and treatment trials of these patients.