OA1: from molecular bases to gene delivery

描述(申请人提供)：眼白化病1型的特征是视力受损，眼球震颤，畏光，斜视和立体视觉丧失。它被遗传为X染色体连锁的性状。与其他类型的白化病相似，它与发育过程中视束的错误走行有关。该疾病的组织病理学特征是在皮肤黑素细胞和视网膜色素上皮(RPE)中都存在巨大的黑素小体。在鉴定了OA1基因之后，在患者中发现了几个功能丧失的突变。然而，这些约占所研究病例的70%，其余突变到目前为止还没有被检测到。OA1蛋白产物与G蛋白偶联受体序列相似，并与G蛋白结合。与该蛋白家族的大多数成员不同，OA1位于细胞内，位于黑素体膜上。眼部白化病大黑素小体的表型和OA1蛋白的亚细胞定位均提示黑素小体的生物发生存在缺陷。然而，OA1在这一基本过程中的确切作用仍不清楚。研究OA1功能和疾病发病机制的一个重要模型系统是OA1基因敲除小鼠，它概括了人类疾病的表型。本项目的目标是：1)确定导致疾病的全谱突变，2)研究OA1在视觉系统发育和维护过程中的需求，3)发现OA1基因突变导致疾病表型的致病步骤，4)表征OA1与其他参与白化病的基因的功能相互作用，以了解它们在黑素小体生物发生中的作用，5)建立出生前和出生后OA1基因传递到动物模型的RPE的方法，分别针对表型预防和拯救。这些研究将促进我们对OA1在色素沉着、RPE功能、黑素小体生物发生和视神经发育中的作用的理解。此外，他们将导致对眼部白化病1型的发病机制以及其他类型的白化病有更深入的了解。最后，所开发的基因传递方法可能是未来治疗涉及RPE的眼病的重要工具。

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.