The function of proteins associated with albinism

与白化病相关的蛋白质的功能

• 批准号: 6928454
• 负责人: MURRAY H BRILLIANT
• 金额: $ 18.81万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6928454
• 关键词: Xenopus oocyte; acidity /alkalinity; albinism; biological transport; biophysics; biosynthesis; cell component structure /function; chlorine; laboratory mouse; melanins; melanocyte; melanosomes; membrane transport proteins; molecular pathology; osmosis; phosphorylation; protein structure function; tyrosine; voltage /patch clamp

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.

描述（由申请人提供）：该项目的总体目标是了解与眼皮肤白化病（分别为 OCA2 和 OCA4）相关的 P 和 MATP 基因编码的蛋白质的功能。 p 和 Matp 蛋白预计具有 12 个跨膜结构域，并且均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有关，Matp 与植物质子/糖同向转运蛋白有关。这些蛋白质可能介导溶质穿过黑素体（合成和储存黑色素的黑素细胞器）或前体囊泡膜的运输。要研究的两种蛋白质由小鼠基因粉红眼睛稀释 (p) 和白底白 (uw) 编码，并由几个有用的突变等位基因定义。这项研究对人类健康有直接影响，因为 OCA2（酪氨酸酶阳性眼皮肤白化病）是最常见的白化病形式之一。 OCA2 在医疗服务不足的人群中尤其常见，包括非裔美国人和美洲原住民（例如，大约每 250 名霍皮族或祖尼印第安人中就有 1 人患有 OCA2）。 OCA4 最近才被描述，它是由 MATP 基因（人类 Underwhite 的同源基因）突变引起的。与所有其他形式的白化病一样，OCA2 和 OCA4 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个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：利用生物物理方法确定它们各自蛋白质的功能。了解这些蛋白质的功能将有助于深入了解膜运输机制在黑素体生物发生和黑色素生物合成中的作用。黑素细胞和色素性视网膜上皮细胞中这些过程的破坏会导致白化病及其相关的视觉系统缺陷。这些色素沉着不足疾病的小鼠模型的表征将提供一个系统来测试遗传和生化干预在治疗同源人类疾病中的功效。