White mutants in mice shedding light on humans.
White mutants in mice shedding light on humans.
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DOI：
10.1038/jid.1993.73
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发表时间：
1993-02
期刊：
影响因子：
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通讯作者：
Ruth Halaban;Gisela Moellmann
中科院分区：
文献类型：
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作者：
Ruth Halaban;Gisela Moellmann
在这篇文章中，我们描述了三种遗传性色素沉着疾病的分子遗传学的快速进展：白化病，花斑病，白癜风，所有这些都揭示了正常的色素细胞功能。重点是小鼠研究，并与人类数据进行比较。酪氨酸酶（c-位点或人酪氨酸酶蛋白）在正常色素沉着和白化病中的关键作用已经通过酪氨酸酶和另外两种在结构上与酪氨酸酶相关但在功能上与酪氨酸酶不同的黑素细胞特异性氧化还原酶（B）中的突变的克隆和鉴定而得到加强：（b）棕色位点蛋白/gp 75/过氧化氢酶和多巴色素互变异构酶。每一种都具有不同的酶活性，但这三种酶在关键区域具有同源性。大多数降低或消除相应酶活性的点突变位于这些区域。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基因座最近被定位到染色体15q11.2 → q12，在小鼠斜视稀释中鉴定的基因处。另一方面，已知几种编码对黑素细胞增殖至关重要的蛋白质的基因控制花斑表型。到目前为止，已确定了两种膜受体酪氨酸激酶，c-Kit和PDGF-R/α，以及配体forc-kit，MGF（肥大细胞生长因子，也称为干细胞因子，c-Rit-配体或钢因子）。W/c-kit（白色斑点）、Ph/ Pdgfr/a（斑点）和Sl/MGF（钢）中的突变导致受体激酶活性的降低和黑素细胞在胚胎发生期间不能茁壮成长并到达皮肤。最后，小鼠突变模型表明白癜风至少有两种可能的原因，即出生后发生的色素沉着的进行性丧失。在一个突变体中，Blt（轻）小鼠，毛发黑素细胞的周期性死亡可能是由于在功能障碍的b基因座蛋白存在下黑素生成的中间产物和副产物的毒性。在另一个模型中，“白癜风小鼠”，其中等位基因被分配到小眼（mi）位点，黑素细胞的损失可能是由缺陷的信号转导引起的，因为除了白癜风/mivit小鼠有广泛的斑驳病。
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/catalaseBand dopachrome tauto-merase. 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 aspink-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/α, and the ligand forc-kit, MGF (mast-cell growth factor, also known as stem-cell factor, c-Rit-ligand, or steel factor). Mutations in W/c-kit (white spotting), Ph/ Pdgfr/a (patch), andSl/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, theBlt (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 dysfunctionalb-locus protein. In the other model, the “vitiligo mouse,” in which the allelevithas been assigned to the microphthalmia(mi)locus, the loss of melanocytes may be caused by defective signal transduction, because in addition to vitiligomivit/mivitmice have extensive piebaldism.