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The disease model of the new discovery atopic dermatitis mouse and the positional cloning of the responsibility gene

新发现特应性皮炎小鼠疾病模型及责任基因的定位克隆

基本信息

批准号：
16390292
负责人：
MATSUSHIMA Yoshibumi
金额：
$ 4.74万
依托单位：
Saitama Cancer Center
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2006
项目状态：
已结题

项目摘要

Atopic dermatitis (AD) is a hereditary pruritic chronic relapsing eczematous dermatitis resulted from complex interactions between genetic and environmental factors, and is frequently associated with elevated levels of serum IgE. While much effort was made to elucidate the pathogenesis, it remains to be elusive and responsible genes are not identified. Hence, establishment of animal models for hereditary AD is an urgent issue: We here report the establishment of a new mouse model, named Nippon atopic dermatitis (NAD) mice, and the mapping of responsible gene.1. NAD mice were derived from KOR mice, an inbred strain of Mus musclus molossinus, and their phenotype was transmitted in an autosomal recessive manner. The phenotype of NAD mice kept in SPF environment first appeared as edematous skin change at eyelids at the age of 4-5 weeks with elevation of serum IgE. The edema spread to other face regions, head and forefoot ; the affected skin is infiltrated with mast cell and eventually developed erosion, ulceration and loss of hairs. These clinical characteristics are distinct from those of NC mice, another mouse model of AD : Breeding test revealed that the alleles of NAD and NC mice are different.2. Linkage analysis using F2 between NAD and BALB/c revealed that the responsible gene localizes on chromosome 10 close to D10Mit53 and D10Mit109. Interestingly, human chromosomal region syntenic ton this region, 6q22-23, contains the INFgR and TNFaIP3 genes, which may be responsible genes for AD. Further study of NAD mice will contribute to elucidate the pathogenesis of AD.3. A novel mutant that showed human atopic dermatitis-like phenotypes was found in a colony of the inbred mouse strain KOR. Positional cloning revealed that the mouse homologue of human Traf3ip2 protein, carried a single point mutation leading to the substitution of^214glutamine for nonsense codon. This indicated that Traf3ip2 played an important role in the homeostasis of epithelial cells and B cells

特应性皮炎（AD）是一种遗传性瘙痒性慢性复发性湿疹性皮炎，是遗传和环境因素复杂相互作用的结果，通常与血清IgE水平升高有关。虽然已经做出了很多努力来阐明发病机制，但它仍然是难以捉摸的，并且没有确定负责的基因。因此，建立遗传性AD的动物模型是一个紧迫的问题：我们在此报道建立了一种新的小鼠模型，命名为Nippon特应性皮炎（NAD）小鼠，并定位了相关基因1。NAD小鼠来源于小家鼠近亲系KOR小鼠，其表型以常染色体隐性遗传方式遗传。SPF环境下NAD小鼠的表型首先表现为4-5周龄眼睑皮肤水肿改变，血清IgE升高。水肿扩散至面部其他区域、头部和前足；受影响的皮肤被肥大细胞浸润，最终发展成糜烂、溃疡和脱发。这些临床特征与NC小鼠不同，NC小鼠是AD的另一种小鼠模型：育种试验显示NAD与NC小鼠的等位基因不同。利用F2对NAD和BALB/c基因进行连锁分析，发现相关基因位于靠近D10Mit53和D10Mit109的10号染色体上。有趣的是，与该区域同源的人类染色体区域6q22-23含有可能与AD相关的INFgR和TNFaIP3基因。对NAD小鼠的进一步研究将有助于阐明AD.3的发病机制。在近亲繁殖的小鼠菌种KOR中发现了一种显示人类特应性皮炎样表型的新突变体。定位克隆发现，人类Traf3ip2蛋白的小鼠同源物携带单点突变，导致^214谷氨酰胺取代无义密码子。这表明Traf3ip2在上皮细胞和B细胞的稳态中起重要作用