MOLECULAR GENETICS OF HAILEY-HAILEY DISEASE

Hailey-Hailey病是一种不寻常的起泡性皮肤病， 常染色体显性特征 其典型的组织学异常是 棘层松解-表皮中部角质形成细胞的凝聚力丧失。 由于这种凝聚力对联合国运作的重要性， 复层鳞状上皮，由于过去缺乏成功的 为了了解这种疾病的基础，我们提出了一个 分子遗传学方法研究这种疾病。 前需要符合的 这个建议，我们已经使用连锁分析在四个大海利-海利 排除候选基因的家族-那些编码克隆蛋白的家族 可能对角质形成细胞的凝聚力很重要， 染色体3q。 我们现在的具体目标是（A）招募更多的海利-海利 患者和进一步缩小Hailey-Hailey基因区域（B）物理 遗传上限定的Hailey-Hailey病基因区的定位， Hailey-Hailey基因的鉴定（C）突变的鉴定 在Hailey-Hailey基因中的多激酶和（D）建立 全细胞和全动物模型证明了 突变Hailey-Hailey基因产物的表达。 成功 这些研究的完成不仅将揭示潜在的缺陷， 这种典型的遗传性皮肤病，并希望由此导致新的，有效的 这些患者的治疗，但也应该提供重要的新的 了解角质形成细胞间凝聚的机制， 对复层鳞状上皮的完整性至关重要

Hailey-Hailey disease is an unusual blistering skin disease inherited as an autosomal dominant trait. Its characteristic histologic abnormality is acantholysis - the loss of cohesion of keratinocytes of the mid epidermis. Because of the importance of that cohesion to the functioning of stratified squamous epithelia and because of the past lack of success of efforts to understand the basis of this disease, we are proposing a molecular genetics approach to the study of this disease. Preliminary to this proposal we have used linkage analysis in four large Hailey-Hailey families to exclude candidate genes - those encoding cloned proteins possibly important in keratinocyte cohesion - and to localize the gene to chromosome 3q. Our specific aims now are (A) recruitment of additional Hailey-Hailey patients and narrowing further the Hailey-Hailey gene region (B) Physical mapping of the genetically-delimited Hailey-Hailey disease gene region and identification of the Hailey-Hailey gene (C) Identification of mutations in the Hailey-Hailey gene in multiple kindreds and (D) Establishment of whole celll and whole animal models demonstrating the effects of the expression of mutant Hailey-Hailey gene products. The successful completion of these studies not only will illuminate the defect underlying this classical genodermatosis and hopefully thereby lead to new, effective therapies for these patients but also should afford important new undestandings of the mechanisms of inter-keratinocyte cohesion, which is so critical to the integrity of all stratified squamous epithelia.