Isolation of congenital stationary night blindness genes

描述(申请人提供)：当光在感光器中被转换成电信号时，视觉开始。光的增加减少了神经递质谷氨酸从视锥和视杆感光终末的释放，而光的减少则增加了它的释放。突触谷氨酸浓度的这些变化是由两类双极细胞检测到的，然后它们通过视网膜电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。有两类双极细胞，超极化(HBCS)和去极化(DBCS)。HbC利用离子型谷氨酸受体并对闪光做出反应而超极化。DBCS利用一种代谢性谷氨酸受体mGluR6，并对闪光做出反应而去极化。光感受器和双极细胞之间的传输缺陷会导致几种形式的先天性静止性夜盲(CSNB)。这种不完整的形式CSNB2是由光感受器中关键的谷氨酸释放基因突变造成的，包括电压依赖性钙通道的11F亚单位。完整的形式出现在DBCS的信号突变中，其中包括mGluR6和Nyctalopin(一种功能未知的蛋白质)的突变。通过DBCS的信号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级联的细节大多是未知的。该项目的长期目标是确定光感受器和DBCS之间突触传递所需的分子组成。本项目有四个具体目标：1)确定nyctalopin的结构/功能关系，2)确定几只夜盲小鼠的非特异性阳离子通道的状态，3)确定nyctalopin的结合伙伴，从而阐明mGluR6级联的新成分，以及4)建立nyctalopin相互作用蛋白的敲除小鼠系，以确定它们是否导致近盲。在这个项目完成后，我们将确定对DBCS中的信号传输至关重要的新成员。此外，我们还将确定先天性静止性夜盲的新候选基因。 与公共健康相关：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。正在研究的一组疾病被称为先天性静止性夜盲。它们在光感受器和通路中的第二神经元之间的信号传递方面存在缺陷。这项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.