Ocular Albinism type 1: from molecular bases to gene delivery

描述（由申请人提供）：1型眼白化病的特征为视力受损、眼球震颤、斜视、斜视和立体视觉丧失。它是作为X染色体连锁性状遗传的。与其他类型的白化病相似，它与发育过程中视神经束的错误路由有关。该疾病的组织病理学标志是皮肤黑素细胞和视网膜色素上皮（RPE）中存在大黑素体。在OA1基因的鉴定之后，在患者中鉴定了几种功能丧失突变。然而，这些占研究病例的约70%，其余突变迄今未被检测到。OA 1蛋白产物与G蛋白偶联受体具有序列相似性并结合G蛋白。与该蛋白家族的大多数成员不同，OA1是细胞内的，位于黑素体膜上。大黑素体表型和OA1蛋白的亚细胞定位都表明眼白化病中黑素体生物发生的缺陷。然而，OA1在这一基本过程中的确切作用仍然未知。研究OA1功能和疾病发病机制的重要模型系统是OA1敲除小鼠，其重现了人类疾病表型。该项目的目标是：1）鉴定引起该疾病的突变的全谱，2）研究视觉系统发育和维持过程中OA1的需求，3）发现从OA1基因突变到疾病表型的发病步骤，4）表征OA1与参与白化病的其他基因的功能相互作用以理解它们在黑素体生物发生中的作用，5）开发针对动物模型的RPE的产前和纳塔尔OA1基因递送方法，分别旨在表型预防和拯救。这些研究将促进我们对OA1在色素沉着、RPE功能、黑素体生物发生和视神经发育中的功能的理解。此外，他们将导致更深入地了解眼白化病1型以及其他类型的白化病的发病机制。最后，开发的基因递送方法可能是未来治疗涉及RPE的眼部疾病的重要工具。

DESCRIPTION (provided by applicant): Ocular albinism type 1 is characterized by impaired visual acuity, nystagmus, photophobia, strabismus and loss of stereoscopic vision. It is inherited as an X chromosome-linked trait. Similarly to other types of albinism, it is associated with misrouting of the optic tracts during development. The histopathological hallmark of the disease is the presence of macromelanosomes in both skin melanocytes and retinal pigment epithelium (RPE). Following identification of the OA1 gene, several loss-of-function mutations were identified in patients. However, these account for approximately 70% of the cases studied, the remaining mutations being so far undetected. The OA1 protein product shares sequence similarity with G-protein coupled receptors and binds G proteins. Unlike most members of this protein family, OA1 is intracellular, being located on the melanosomal membrane. Both the macromelanosomal phenotype and the subcellular localization of the OA1 protein suggest a defect in melanosome biogenesis in ocular albinism. However, the precise role of OA1 in this fundamental process is still unknown. An important model system to study OA1 function and disease pathogenesis is the OA1 knock-out mouse which recapitulates the human disease phenotype. The goals of this project are to: 1) identify the full spectrum of mutations causing the disease, 2) study the requirement of OA1 during visual system development and maintenance, 3) discover the pathogenetic steps leading from mutations of the OA1 gene to disease phenotype, 4) characterize the functional interaction of OA1 with other genes involved in albinism to understand their role in melanosome biogenesis, 5) develop both pre- and post- natal OA1 gene delivery approaches to the RPE of animal models, aiming at phenotype prevention and rescue, respectively. These studies will advance our understanding of OA1 function in pigmentation, RPE function, melanosome biogenesis, and optic nerve development. In addition, they will lead to a deeper understanding of the pathogenesis of ocular albinism type 1 as well as of other types of albinism. Finally, the gene delivery approaches developed may represent important tools for future treatment of eye diseases involving RPE.