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。增加光减少神经递质谷氨酸从视锥和视杆感光体末端的释放，并且减少光增加其释放。突触谷氨酸浓度的这些变化被两类双极细胞检测到，然后通过视网膜回路将信号垂直传输到神经节细胞。神经递质的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（HBC）和去极化（DBC）。HBCs利用离子型谷氨酸受体和高血压来响应闪光。DBCs利用代谢型谷氨酸受体mGluR 6和去甲肾上腺素来响应闪光。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）。不完整的形式，CSNB 2，是由对光感受器中谷氨酸释放至关重要的基因突变引起的，包括电压依赖性钙通道的11 F亚基。完整的形式出现在DBCs的信号突变中，其中包括mGluR 6和nytalopin（一种功能未知的蛋白质）的突变。通过DBCs的信号传导通过代谢型谷氨酸受体mGluR 6介导，其调节未知身份的非特异性阳离子通道的活性。这种mGluR 6级联的细节大多是未知的。这个项目的长期目标是表征光感受器和DBCs之间突触传递所需的分子组分。该项目有四个具体目标：1）确定夜盲素的结构/功能关系，2）确定几只夜盲小鼠中非特异性阳离子通道的状态，3）确定夜盲素的结合伴侣，从而阐明mGluR 6级联的新组分，以及4）创建夜盲素相互作用蛋白质的敲除小鼠系，以确定它们是否导致夜盲症。在这个项目完成后，我们将确定新的成员在DBCs中的信号传输至关重要。此外，我们还将发现先天性静止性夜盲症的新候选基因。 公共卫生相关性：视觉需要将光信号转换为电信号，然后通过神经网络传输到大脑。正在研究的这组疾病被称为先天性静止性夜盲症。它们在光感受器和通路中的第二神经元之间的信号传递中存在缺陷。该提案中的研究将表征缺陷的性质，并确定对功能至关重要的新蛋白质。

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.