MOUSE MODELS OF ALBINISM

人类色素形成缺陷，包括眼皮肤白化病 是常见的遗传异常， 方面的影响. 皮肤中黑色素生成的减少会导致 对紫外线的敏感性和皮肤癌的易感性。 在发育过程中眼睛中黑色素的减少与生命有关- 长眼震、中心凹发育不全伴视力下降和异常 从视网膜到大脑的神经连接的路由， 斜视和双眼视觉丧失。 的临床特点 已经描述了六种或多种类型的人眼皮肤白化病， 现在很清楚，其中一些是由不同的突变引起的， 单个基因座（等位基因异质性），而其他基因座则由突变引起 基因座异质性（Locus heterogeneity） 本项目的总体目标是研究临床， 眼科、血液学、流行病学、生物化学和分子学 正常和异常人类色素形成的特征，特别是 眼皮肤白化病 这些研究将提供信息， 希望能带来准确诊断、治疗和家庭的方法 咨询，以便这些遗传疾病可以预防，治疗，或 改善。 为此将利用四个项目和一个核心设施 工作 项目1将分析的分子和生化特性， 不同类型的酪氨酸酶相关的眼皮肤白化病。 项目 2将分析调节机制和膜的缺陷， 血小板和血细胞色素减退患者，包括 赫-普二氏综合征 项目3将分析人类与 老鼠的粉红色眼睛的稀释基因，并将寻找一种类型的人类 眼皮肤色素减退与这种变化有关， 基因 项目4将分析黑素细胞的生物学特性， 不同类型的人类眼皮肤白化病。 核心设施将 为以下患者的眼科评价提供支持： 不同的项目，对结构进行生物物理分析， 功能的黑色素分离在不同的项目，并为 开发色素沉着的转基因小鼠模型， 分析黑色素对视神经发育的影响， 听觉系统

Human deficiencies of pigment formation, including oculocutaneous albinism are common genetic abnormalities with severe cutaneous and optic system effects. A reduction of melanin production in the skin results in a marked sensitivity to ultraviolet radiation and a predisposition of skin cancer. Reduction of melanin in the eye during development is associated with life- long nystagmus, foveal hypoplasia with reduced visual acuity, and abnormal routing of the neural connections from the retina to the brain, resulting in strabismus and loss of binocular vision. The clinical characteristics of six or more types of human oculocutaneous albinism have been described, and it is now clear that some of these result from different mutations at a single locus (allele heterogeneity), while others result from mutations at different loci (locus heterogeneity). The overall aims of this project are to investigate the clinical, ophthalmological, hematological, epidemiological, biochemical and molecular features of normal and abnormal human pigment formation, particularly oculocutaneous albinism. These studies will provide information which we hope will lead to methods of accurate diagnosis, therapy, and family counseling, so that these genetic diseases can be prevented, treated, or ameliorated. Four projects and a core facility will be utilized for this work. Project 1 will analyze the molecular and the biochemical characteristics of the different types of tyrosinase-related oculocutaneous albinism. Project 2 will analyze the defects in regulatory mechanisms and membranes in platelets and blood cells in patients with hypopigmentation, including the Hermansky-Pudlak syndrome. Project 3 will analyze the human correlate of the mouse pink-eyed dilution gene and will look for a type of human oculocutaneous hypopigmentation that is associated with changes in this gene. Project 4 will analyze the biology of the melanocyte int he different types of human oculocutaneous albinism. The core facility will provide support for the ophthalmologic evaluation of the patients seen in the different projects, for the biophysical analysis of the structure and function of the melanin isolated in the different projects, and for the development of a transgenic mouse model of pigmentation that can be used in the analysis of the effects of melanin on the development of the optic and auditory system.