GENETIC STUDIES OF HUMAN PIGMENTATION DISORDERS

我们之前已经定义了两个完全不同的分子基础 人类遗传性色素沉着障碍；I型(酪氨酸酶缺陷) 眼皮肤白化病与花斑病。I型OCA是一种临床上 严重的常染色体隐性遗传病，全身性缺陷 色素细胞中黑色素的生物合成是由于活性不足所致 黑素细胞酪氨酸酶。相反，花斑病是一种常染色体 一种显性疾病，表现为皮肤广泛的无色素区域， 由于黑素细胞的缺陷增殖或迁移 胚胎发生，由细胞受体缺陷所致 肥大/干细胞生长因子。我们计划继续对这些问题进行研究 两种疾病。我们将在2003年研究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， 并将这些发现应用于改进的携带者检测和 这种疾病的产前诊断。特异性酪氨酸酶的作用 多重催化和铜结合上的基因错义替换 酪氨酸酶的活性也将被研究，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，鉴定额外的突变 C-kit原癌基因在本病患者中的表达。的相关性 具有相关表型的C-KIT基因突变可以识别 相应酪氨酸激酶生长中的重要功能部位 因子受体。我们还计划启动一个长期项目，以确定 第三种临床重要疾病的分子基础 色素沉着，瓦登堡综合征，I型，一种发育障碍 表型与花斑病相似，但影响范围更广 神经沟来源的细胞谱系的阵列，导致白色 斑点、耳聋和面部变形。

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.