Tomita Y, Miyamura Y, Kono M, Nakamura R, Matsunaga J
Department of Dermatology, Nagoya University School of Medicine, Japan.
Pigment Cell Res. 2000;13 Suppl 8:130-4. doi: 10.1034/j.1600-0749.13.s8.23.x.
The molecular bases of various types of congenital hypopigmentary disorders have been clarified in the past 10 years. Homozygous gene mutations of enzymes functional in melanogenesis such as tyrosinase, P protein and DHICA oxidase, result in oculocutaneous albinism (OCA) 1, OCA 2, and OCA 3, respectively. The genes responsible for Hermansky-Pudlak syndrome (HPS) and Chediak-Higashi syndrome (CHS) have also recently been isolated and cloned. The transcription factor paired box 3 (PAX3) works at the promoter region of the microphthalmia-associated transcription factor (MITF) gene, and the MITF transcription factor orders the expression of c-kit, which encodes the receptor for stem-cell factor, which in turn stimulates melanoblast migration from the neural tube to the skin in the embryo. Heterozygous mutations of PAX3, MITF, or c-kit genes induce Waardenburg syndrome (WS) 1/3, WS 2 or Piebaldism, respectively. A defect of endothelin-3 or the endothelin-B receptor produces WS 4. In our examination of 26 OCA 1 patients in Japan, all were found to have homozygous or heterozygous tyrosinase gene mutations at codons 77 or 310. Therefore, mutations at codons 77 and 310 are the major ones in Japanese patients with OCA 1. An autosomal dominant pigmentary disease of dyschromatosis symmetrica hereditaria (DSH) is well known in Japan, and is characterized by a mixture of hypo- and hyper-pigmented macules of various sizes on the backs of the hands and feet. The disease gene and its chromosomal localization have not been identified yet. Our trial of linkage analysis and positional cloning to determine the disease gene is presented.
在过去10年里，各种类型先天性色素减退症的分子基础已被阐明。在黑素生成中发挥作用的酶，如酪氨酸酶、P蛋白和二羟基吲哚羧酸氧化酶的纯合基因突变，分别导致眼皮肤白化病（OCA）1型、OCA 2型和OCA 3型。最近，还分离并克隆了与Hermansky-Pudlak综合征（HPS）和Chediak-Higashi综合征（CHS）相关的基因。转录因子配对盒3（PAX3）在小眼畸形相关转录因子（MITF）基因的启动子区域起作用，而MITF转录因子调控c-kit的表达，c-kit编码干细胞因子的受体，进而刺激胚胎中黑素母细胞从神经管迁移至皮肤。PAX3、MITF或c-kit基因的杂合突变分别导致Waardenburg综合征（WS）1/3型、WS 2型或斑驳病。内皮素-3或内皮素B受体缺陷会导致WS 4型。在我们对26名日本OCA 1型患者的检测中，发现所有患者在77或310密码子处均有纯合或杂合的酪氨酸酶基因突变。因此，77和310密码子处的突变是日本OCA 1型患者的主要突变类型。对称性进行性色素异常症（DSH）是日本一种常见的常染色体显性色素沉着病，其特征是在手背和脚背上有大小不一的色素减退和色素沉着斑混合存在。该病的致病基因及其染色体定位尚未确定。本文介绍了我们通过连锁分析和定位克隆来确定致病基因的尝试。
