Halaban R, Moellmann G
Yale University School of Medicine, Department of Dermatology, New Haven, Connecticut 06510-8059.
J Invest Dermatol. 1993 Feb;100(2 Suppl):176S-185S.
In this article we describe the rapid advances made in the molecular genetics of three inherited pigmentation disorders: albinism, piebaldism, and vitiligo, all of which throw light on normal pigment cell function. The focus is on studies in mice, with comparison of data in humans. The critical role of tyrosinase (c-locus or human tyrosinase protein) in normal pigmentation and albinism has been reinforced by the cloning and identification of mutations in tyrosinase and two other melanocyte-specific oxidoreductases structurally related to but functionally different from tyrosinase: the (b) brown-locus protein/gp75/catalase B and dopachrome tautomerase. Each possesses a distinct enzyme activity and yet the three share homology in strategic regions. Most of the point mutations that reduce or abrogate the respective enzyme activities are located in those regions. Tyrosinase-negative albinism is caused only by defects in tyrosinase. A locus for human tyrosinase-positive albinism has been recently mapped to chromosome 15q11.2-->q12, at a gene identified in mice as pink-eyed dilution. On the other hand, several genes encoding proteins critical for the proliferation of melanocytes are known to control the piebald phenotype. So far identified are two membrane-receptor tyrosine kinases, c-Kit and PDGF-R/alpha, and the ligand for c-kit, MGF (mast-cell growth factor, also known as stem-cell factor, c-Kit-ligand, or steel factor). Mutations in W/c-kit (white spotting), Ph/Pdgfr/a (patch), and Sl/MGF (steel), lead to a reduction in receptor kinase activity and failure of melanocytes to thrive and reach the skin during embryogenesis. Finally, mouse mutant models suggest at least two possible causes for vitiligo, a progressive loss of pigmentation that occurs after birth. In one mutant, the Blt (light) mouse, the cyclic death of hair melanocytes may be due to the toxicity of intermediates and byproducts of melanogenesis in the presence of a dysfunctional b-locus protein. In the other model, the "vitiligo mouse," in which the allele vit has been assigned to the microphthalmia (mi) locus, the loss of melanocytes may be caused by defective signal transduction, because in addition to vitiligo mivit/mivit mice have extensive piebaldism.
在本文中，我们描述了三种遗传性色素沉着障碍（白化病、斑驳病和白癜风）在分子遗传学方面取得的快速进展，所有这些都有助于阐明正常色素细胞的功能。重点是小鼠研究，并与人类数据进行比较。酪氨酸酶（c位点或人类酪氨酸酶蛋白）在正常色素沉着和白化病中的关键作用，通过克隆和鉴定酪氨酸酶以及另外两种与酪氨酸酶结构相关但功能不同的黑素细胞特异性氧化还原酶中的突变而得到加强：（b）棕色位点蛋白/gp75/过氧化氢酶B和多巴色素互变异构酶。每种酶都具有独特的酶活性，但这三种酶在关键区域具有同源性。大多数降低或消除各自酶活性的点突变都位于这些区域。酪氨酸酶阴性白化病仅由酪氨酸酶缺陷引起。人类酪氨酸酶阳性白化病的一个基因座最近已定位到染色体15q11.2→q12，在小鼠中该基因被鉴定为粉红眼稀释基因。另一方面，已知几个对黑素细胞增殖至关重要的蛋白质编码基因控制着斑驳病的表型。到目前为止，已鉴定出两种膜受体酪氨酸激酶，即c-Kit和PDGF-R/α，以及c-kit的配体MGF（肥大细胞生长因子，也称为干细胞因子、c-Kit配体或钢铁因子）。W/c-kit（白斑）、Ph/Pdgfr/a（斑块）和Sl/MGF（钢铁）中的突变会导致受体激酶活性降低，以及黑素细胞在胚胎发育过程中无法茁壮成长并到达皮肤。最后，小鼠突变模型提示了白癜风（一种出生后发生的色素沉着进行性丧失疾病）的至少两种可能病因。在一种突变体Blt（浅色）小鼠中，毛发黑素细胞的周期性死亡可能是由于在功能失调的b位点蛋白存在下黑素生成中间体和副产物的毒性所致。在另一种模型“白癜风小鼠”中，等位基因vit已被指定到小眼症（mi）基因座，黑素细胞的丧失可能是由信号转导缺陷引起的，因为除了白癜风外，mivit/mivit小鼠还有广泛的斑驳病。
