MELANIN BIOSYNTHESIS AND OCULOCUTANEOUS ALBINISM

酪氨酸酶阴性和酪氨酸酶阳性眼皮肤白化病是 常染色体隐性遗传疾病，其中没有色素，或最低限度- 皮肤、头发或眼睛中可检测到的色素。 白化病的发病率 美国的比例约为1：18，000，而黑人人口 发病率很高 我们假设酪氨酸酶阴性的形式 酪氨酸酶基因突变的结果，酪氨酸酶- 阳性形式是由控制基因突变引起的。 真黑素合成途径，酪氨酸酶催化远端。 我们有 分离了人酪氨酸酶基因和候选基因（pmel 17 - 1），其 产物可能参与控制真黑素的生物合成。 在一项对隐性遗传白化病家族的研究中， 在酪氨酸酶基因座中的两个受影响的人中， 和他们正常的兄弟在一起 这项建议的主要目的是 对酪氨酸酶和pmel 17 - 1基因突变类型进行了分类， 酪氨酸酶阴性和酪氨酸酶阳性白化病，并制定一项 用于产前诊断的核酸探针和改进的携带者检测。 为此，我们将确定pmel 17 - 1基因产物的功能 在真黑素生物合成中的作用，并将表征 人酪氨酸酶和pmel 17 - 1基因座。 我们将分析 酪氨酸酶和pmel 17 - 1基因的限制性片段长度多态性 在酪氨酸酶阴性和阳性白化病DNA中， 比较在不同的细胞中的mRNA表达和酪氨酸酶和pmel 17 - 1 cDNA序列， 白化病人和正常人 最后，我们将表达正常和 突变的酪氨酸酶和pmel 17 - 1基因在白化病黑素细胞，以证实 突变导致酶失活。 一旦我们确定了突变体的病理损伤并将其分类， 基因，我们将设计用于产前诊断的核酸探针， 酪氨酸酶阴性和酪氨酸酶阳性的改进的载体检测 眼皮肤白化病

Tyrosinase-negative and tyrosinase-positive oculocutaneous albinisms are autosomal recessive disorders in which there is no pigment, or minimally- detectable pigment, in the skin, hair, or eyes. The incidence of albinism in the United States is approximately 1:18,000, and the black population shows a high incidence. We hypothesize that the tyrosinase-negative form results from mutation of the tyrosinase gene, and that the tyrosinase- positive form results from mutation of the genes which control the eumelanin synthetic pathway, distal to tyrosinase catalysis. We have isolated a human tyrosinase gene and a candidate gene (pmel 17-1), whose product may be involved in controlling the eumelanin biosynthesis. In a study of a recessively-inherited albino family, structural differences in the tyrosinase locus were noted in two of those affected, as contrasted with their normal brother. The primary objective of this proposal is to classify the kinds of mutation in tyrosinase and pmel 17-1 genes in tyrosinase-negative and tyrosinase-positive albinos, and to develop a nucleic acid probe for prenatal diagnosis and improved carrier detection. To this end, we will determine the function of the pmel 17-1 gene product in eumelanin biosynthesis and will characterize the genomic organization of both the human tyrosinase and pmel 17-1 loci. We will analyze the restriction fragment length polymorphisms of tyrosinase and pmel 17-1 genes in tyrosinase-negative and -positive albino DNA, respectively, and will compare the mRNA expression and tyrosinase and pmel 17-1 cDNA sequences in albinos with the normal counterpart. Finally, we will express normal and mutated tyrosinase and pmel 17-1 genes in albino melanocytes, to confirm that the mutations result in the inactivity of the enzymes. Once we have identified and classified the pathologic lesions of mutant genes, we will design nucleic acid probes for prenatal diagnosis and improved carrier detection of tyrosinase-negative and tyrosinase-positive oculocutaneous albinism.