The function of proteins associated with albinism

描述（由申请人提供）：本项目的总体目标是了解与眼皮肤白化病（分别为OCA 2和OCA 4）相关的P和MATP基因编码的蛋白质的功能。P和Matp蛋白被预测具有12个跨膜结构域，并且都显示出与转运蛋白的同源性：P与细菌和酵母阴离子转运蛋白，Matp与植物质子/糖共转运蛋白。这些蛋白质可以介导溶质穿过黑素体（黑素细胞器，其中合成和储存黑素）或前体囊泡的膜的运输。待研究的两种蛋白质由小鼠基因pink-eyed dilution（p）和underwhite（uw）编码，并由几个有用的突变等位基因定义。拟议的研究对人类健康有直接影响，因为OCA 2（酪氨酸酶阳性眼皮肤白化病）是白化病最常见的形式之一。OCA 2在医疗服务不足的人群中尤其常见，包括非洲裔美国人和美洲原住民（例如，约每250个霍皮族或祖尼族印第安人中就有1人患有OCA 2）。OCA 4只是最近才被描述，是由MATP基因突变引起的，MATP基因是人类under white的直系同源物。像所有其他形式的白化病一样，OCA 2和OCA 4与视觉系统的深刻变化有关。在过去的研究中，我们已经克隆或鉴定了这两种基因的小鼠和人类形式，在这里，我们提出了一个新的研究方向：使用生物物理方法确定其各自蛋白质的功能。了解这些蛋白质的功能将导致深入了解膜转运机制在黑素体生物发生和黑色素生物合成中的作用。黑素细胞和色素视网膜上皮细胞中这些过程的破坏导致白化病及其相关的视觉系统缺陷。这些色素减退疾病的小鼠模型的表征将提供一个系统，以测试在同源人类疾病的治疗中的遗传和生化干预的功效。

DESCRIPTION (provided by applicant): The overall objective of this project is to understand the function of the proteins encoded by the P and MATP genes that are associated with forms of oculocutaneous albinism (OCA2 and OCA4, respectively). The p and Matp proteins are predicted to have 12 membrane-spanning domains and both show homology to transport proteins: p to bacterial and yeast anion transporters and Matp to plant proton/sugar symporters. These proteins may mediate the transport of solutes across the membrane of the melanosome (the melanocyte organelle in which melanin is synthesized and stored) or a precursor vesicle. The two proteins to be studied are encoded by the mouse genes pink-eyed dilution (p) and underwhite (uw) and are defined by several useful mutant alleles. The proposed research has a direct bearing on human health, as OCA2 (tyrosinase-positive oculocutaneous albinism) is one of the most common forms of albinism. OCA2 is especially common among medically underserved populations, including African Americans and Native Americans (e.g., approx. 1 in 250 Hopi or Zuni Indians has OCA2). OCA4 has only recently been described and is caused by mutations in the MATP gene, the human orthologue of underwhite. Like all other forms of albinism, OCA2 and OCA4 are associated with profound changes in the visual system. In past studies, we have cloned or identified both the mouse and human forms of these two genes, and here we propose a new direction of research: to determine the function of their respective proteins using biophysical approaches. An understanding of the function of these proteins will lead to insights into the role of membrane transport mechanisms in melanosome biogenesis and melanin biosynthesis. Disruption of these processes in melanocytes and pigmented retinal epithelial cells leads to albinism and its associated visual system defects. The characterization of mouse models for these hypopigmentation disorders will provide a system to test the efficacy of genetic and biochemical intervention in the treatment of the homologous human disorders.