MOLECULAR GENETICS OF HAILEY HAILEY DISEASE

Hailey-Hailey病是一种罕见的水疱性皮肤病，遗传为 一种常染色体显性特征。其特征性组织学异常是 棘层松解--中表皮角质形成细胞失去凝聚力。 因为这种凝聚力对 复层鳞状上皮和由于过去缺乏成功的 为了了解这种疾病的基础，我们提出了一种 用分子遗传学的方法研究这种疾病。初步到 这个建议我们已经在四个大的Hailey-Hailey中使用了连锁分析 排除候选基因的家庭-那些编码克隆蛋白的基因 可能对角质形成细胞的凝聚力很重要--并将该基因定位于 染色体3Q。 我们现在的具体目标是(A)招募更多的Hailey-Hailey 患者和进一步缩小Hailey-Hailey基因区(B)物理 遗传性Hailey-Hailey病基因区的定位 Hailey-Hailey基因的鉴定(C)突变鉴定 多个家系的Hailey-Hailey基因及(D)基因的建立 全细胞和全动物模型演示了 突变型Hailey-Hailey基因产物的表达成功者 这些研究的完成不仅将揭示潜在的缺陷 这种经典的遗传性皮肤病有望带来新的、有效的 这些患者的治疗方法也应该负担得起重要的新技术 了解角质形成细胞间凝聚的机制，这是 对所有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.