Expression and Function of Cone Pigment Genes

描述(申请人提供)：这项研究计划的长期目标是了解氨基酸序列多态在长波长和中波长视锥视蛋白在视力障碍中的作用。在人视紫质或S视锥视蛋白中观察到的所有已知的氨基酸替换都与光感受器异常和疾病有关。我们在这项提案中要解决的问题是--L视锥蛋白和M视锥视蛋白中的氨基酸替换在视力障碍中起什么作用？我们提出了以下具体目标： 具体目的1：研究视锥细胞视蛋白变异与老年性黄斑变性(AMD)的关系。利用数百名AMD患者和数百名匹配的对照组受试者的DNA样本，我们将量化L和M-视蛋白基因序列变异与AMD风险之间的关联。 具体目标2：在视力正常的男性中从未观察到一种名为LVAVA的高频视蛋白变异。它的发生总是与视力障碍有关。患有这种变异的个体表现为病理性近视、视锥ERG异常和视神经发育不良，显示神经节细胞数量减少。我们将在小鼠模型中检测LVAVA变体对视锥感光细胞和其他视网膜细胞的结构和生理的影响，并确定该变体在眼睛中导致其广谱异常的机制。 具体目标3：在视力正常的男性中从未观察到的第二个视锥视蛋白变体，称为Liava，以较高的速度产生。表达这种变体的视锥细胞的功能被破坏，自适应光学成像显示表达该变体的视锥细胞受损或丢失。我们将在小鼠模型中检测Liava突变对视锥感光细胞结构和生理的影响，并确定该变异视蛋白扰乱光感受器功能的机制。

DESCRIPTION (provided by applicant): The long-term goal of this research program is to understand the role of amino acid sequence polymorphisms in the long- and middle-wavelength cone opsins in vision disorders. All known amino acid substitutions observed in human rhodopsin or in the human S cone opsin are associated with photoreceptor abnormalities and disease. The question we will address in this proposal is - what is the role of amino acid substitutions in the L and M cone opsins in vision disorders? We propose the following specific aims: Specific Aim 1: Examine the relationship between cone opsin variants and age related macular degeneration (AMD). Using DNA samples from several hundred subjects with AMD and several hundred matched control subjects we will quantify the association between sequence variations in the L and M opsin genes and risk of AMD. Specific Aim 2: A high frequency opsin variant, designated LVAVA, has never been observed in a male with normal vision. Its occurrence is always associated with vision disorder. Individuals with this variant exhibit pathological myopia, cone ERG abnormalities and optic nerve hypoplasia indicating a reduced number of ganglion cells. We will examine the effects of the LVAVA variant on the structure and physiology of cone photoreceptors and other retinal cells in a mouse model and determine the mechanism by which the variant opsin produces its wide spectrum of abnormalities in the eye. Specific Aim 3: A second cone opsin variant which is never observed in males with normal vision, designated LIAVA, is generated at a high rate. Function is disrupted in cones expressing this variant and adaptive optics imaging demonstrates that cones expressing it are damaged or lost. We will examine the effects of the LIAVA mutation on the structure and physiology of cone photoreceptors in a mouse model and determine the mechanism by which the variant opsin disrupts photoreceptor function.