Expression and Function of Cone Pigment Genes

描述（由申请人提供）：本研究项目的长期目标是了解长波长和中波长视锥细胞视蛋白中氨基酸序列多态性在视觉障碍中的作用。在人视紫红质或人S锥视蛋白中观察到的所有已知氨基酸取代与光感受器异常和疾病相关。我们将解决的问题在这个建议是-什么是在视觉障碍的L和M锥视蛋白中的氨基酸取代的作用？我们提出以下具体目标： 具体目的1：研究视锥蛋白变异体与年龄相关性黄斑变性（AMD）之间的关系。使用来自数百名患有AMD的受试者和数百名匹配的对照受试者的DNA样本，我们将量化L和M视蛋白基因中的序列变异与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称为LVAVA的高频视蛋白变体。它的发生总是与视力障碍有关。具有这种变体的个体表现出病理性近视、视锥ERG异常和视神经发育不全，表明神经节细胞数量减少。我们将在小鼠模型中研究LVAVA变体对锥状光感受器和其他视网膜细胞的结构和生理学的影响，并确定变体视蛋白在眼睛中产生广泛异常的机制。 具体目标3：在具有正常视力的男性中从未观察到的第二种视锥视蛋白变体（称为LIAVA）以高速率产生。表达这种变体的视锥细胞功能被破坏，自适应光学成像表明表达这种变体的视锥细胞受损或丢失。我们将在小鼠模型中研究LIAVA突变对锥状光感受器的结构和生理学的影响，并确定变异视蛋白破坏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.