GENETIC STUDIES OF HUMAN PIGMENTATION DISORDERS

我们以前已经定义了两种完全不同的分子基础， 人类遗传性色素沉着病; I型（酪氨酸酶缺乏） 眼皮肤白化病（OCA）和花斑病。I型OCA是临床上 严重的常染色体隐性遗传疾病， 色素细胞中黑色素的生物合成是由于缺乏活性 黑素细胞酪氨酸酶。与此相反，花斑病是一种常染色体 显性疾病，其中皮肤的广泛非色素沉着区域， 由于黑素细胞在生长过程中的增殖或迁移缺陷， 胚胎发生，由于细胞受体缺陷， 肥大/干细胞生长因子。我们计划继续研究这些 两种失调我们会研究I型OCA的分子基础， 几个不同的种族群体，至少包括高加索人，黑人， 和阿拉伯人，并将这些发现应用于改进携带者检测， 这种疾病的产前诊断特异性酪氨酸酶的作用 基因错义置换对多重催化和铜结合 酪氨酸酶的活动也将进行研究，导致详细的 这种酶的分子知识。我们还将继续研究 花斑病的分子基础，确定其他突变， c-kit原癌基因在这种疾病的患者。相关性 具有相关表型的c-kit基因突变可以识别 在相应的酪氨酸激酶生长的功能重要的网站 因子受体我们还计划启动一个长期项目， 第三种临床上重要的疾病的分子基础， 色素沉着，Waardenburg综合征，I型，一种发育障碍 表型上类似于花斑病，但影响范围更广， 一系列神经嵴衍生的细胞谱系，导致白色 斑点耳聋和面部畸形

We have previously defined the molecular basis of two quite different human genetic disorders of pigmentation; type I (tyrosinase-deficient) oculocutaneous albinism (OCA) and piebaldism. Type I OCA is a clinically severe autosomal recessive disorder in which globally defective biosythesis of melanin in pigment cells results from deficient activity of melanocyte tyrosinase. In contrast, piebaldism is an autosomal dominant disorder in which extensive non-pigmented regions of the skin, due to defective proliferation or migration of melanocytes during embryogenesis, result from defects of the cellular receptor for mast/stem cell growth factor. We plan to continue our studies of these two disorders. We will study the molecular basis of type I OCA in several different ethnic groups, including at least Caucasians, Blacks, and Arabs, and apply these findings to improved carrier detection and prenatal diagnosis for this disorder. The effects of specific tyrosinase gene missense substitutions on the multiple catalytic and copper-binding activities of tyrosinase will also be studied, leading to detailed molecular knowledge of this enzyme. We will also continue our studies of the molecular basis of piebaldism, identifying additional mutations of the c-kit proto-oncogene in patients with this disorder. Correlation of c-kit gene mutations with the associated phenotype may identify functionally important sites in the corresponding tyrosine kinase growth factor receptor. We also plan to initiate a long-term project to define the molecular basis of a third clinically important disorder of pigmentation, Waardenburg syndrome, type I, a developmental disorder phenotypically similar to piebaldism, but which affects a somewhat wider array of neural crest-derived cell lineages, resulting in white spotting, deafness, and facial dysmorphia.