Isolation of congenital stationary night blindness genes

描述（由申请人提供）：当光在光感受器中转换为电信号时，视觉开始。光的增加减少神经递质谷氨酸的释放，从锥体和杆状光感受器末端，光的减少增加其释放。突触谷氨酸浓度的变化由两类双极细胞检测，然后将信号垂直地通过视网膜回路传递给神经节细胞。神经递质变化也被水平细胞检测到，水平细胞以反馈和前馈抑制的形式提供横向传递。双极细胞分为两类，超极化细胞（hbc）和去极化细胞（DBCs）。HBCs利用嗜离子性谷氨酸受体，并在闪光灯下超极化。DBCs利用代谢性谷氨酸受体mGluR6，并在光照下去极化。光感受器和双极细胞之间的传输缺陷导致几种形式的先天性静止性夜盲症（CSNB）。CSNB2的不完全形式是由光感受器中谷氨酸释放关键基因的突变引起的，包括电压依赖性钙通道的11F亚基。完整的形式出现在DBCs的信号突变中，包括mGluR6和夜色素（一种功能未知的蛋白质）的突变。通过DBCs的信号传导是通过代谢性谷氨酸受体mGluR6介导的，该受体调节身份未知的非特异性阳离子通道的活性。这个mGluR6级联的细节大部分是未知的。该项目的长期目标是表征光感受器和dbc之间突触传递所需的分子成分。本项目有四个具体目标：1)确定夜酞肽的结构/功能关系，2)确定几种夜盲小鼠的非特异性阳离子通道状态，3)确定夜酞肽的结合伙伴，从而阐明mGluR6级联的新组分，4)创建夜酞肽相互作用蛋白的敲除小鼠系，以确定它们是否导致夜盲。在该项目完成后，我们将确定对dbc信号传输至关重要的新成员。此外，我们将确定先天性静止性夜盲症的新候选基因。

DESCRIPTION (provided by applicant): Vision begins when light is converted to an electrical signal in the photoreceptors. Increases in light decrease release of the neurotransmitter, glutamate, from cone and rod photoreceptor terminals, and decreases in light increase its release. These changes in synaptic glutamate concentration are detected by two classes of bipolar cells that then transmit the signal vertically through the retinal circuit to the ganglion cells. The neurotransmitter changes also are detected by horizontal cells that provide lateral transmission in the form of feedback and feedforward inhibition. There are two classes of bipolar cells, hyperpolarizing (HBCs) and depolarizing (DBCs). HBCs utilize ionotropic glutamate receptors and hyperpolarize in response to a light flash. DBCs utilize a metabotropic glutamate receptor, mGluR6, and depolarize in response to a light flash. Defects in transmission between photoreceptors and bipolar cells result in several forms of congenital stationary night blindness (CSNB). The incomplete form, CSNB2, results from mutations in genes critical to glutamate release in photoreceptors, including the 11F subunit of voltage dependent calcium channels. The complete form emerges from mutations in signaling in DBCs, which include mutations in mGluR6 and nyctalopin (a protein of unknown function). Signaling through DBCs is mediated via a metabotropic glutamate receptor, mGluR6, which modulates the activity of a non-specific cation channel of unknown identity. The details of this mGluR6 cascade are mostly unknown. The long term goal of this project is to characterize the molecular components required for synaptic transmission between photoreceptors and DBCs. This project has four specific aims: 1) determine the structure/function relationships of nyctalopin, 2) determine the state of the non-specific cation channel in several night blind mice, 3) determine the binding partners of nyctalopin, thereby elucidating new component of the mGluR6 cascade, and 4) create knockout mouse lines of the nyctalopin interacting proteins to determine if they result in nigh blindness. At the completion of this project, we will have identified new members critical to signal transmission in DBCs. Further, we will have identified new candidate genes for congenital stationary night blindness. PUBLIC HEALTH RELEVANCE: Vision requires a light signal to be converted to an electrical signal, which is then transmitted to the brain via a neuronal network. The group of diseases being studied is referred to as congenital stationary night blindness. They have defects in signal transmission between photoreceptors and the second neuron in the pathway. The studies in this proposal will characterize the nature of the defects and determine new proteins critical to function.