MOLECULAR GENETICS OF HAILEY-HAILEY DISEASE

Hailey-Hailey 病的分子遗传学

• 批准号: 2082726
• 负责人: Ervin HAROLD Epstein
• 金额: $ 19.58万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-07-15 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2082726
• 关键词: autosomal dominant trait; cell adhesion; family genetics; gene expression; gene mutation; genetic disorder; genetic mapping; human subject; keratinocyte; molecular pathology; tissue /cell culture; vesicular skin disorder

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.

Hailey-Hailey 病是一种不寻常的水疱性皮肤病，遗传性为 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内聚力丧失。 由于这种凝聚力对于组织运作的重要性 复层鳞状上皮，并且由于过去缺乏成功 为了了解这种疾病的基础，我们提出了一种 分子遗传学方法来研究这种疾病。 初步到 这个提案我们在四个大的 Hailey-Hailey 中使用了连锁分析 排除候选基因的家族 - 那些编码克隆蛋白质的基因 可能对角质形成细胞的凝聚力很重要 - 并将该基因定位到 染色体 3q。 我们现在的具体目标是 (A) 招募更多 Hailey-Hailey 患者并进一步缩小 Hailey-Hailey 基因区域 (B) 物理 基因界定的 Hailey-Hailey 病基因区域的图谱和 Hailey-Hailey 基因的鉴定 (C) 突变的鉴定 在多个家族的 Hailey-Hailey 基因中，以及 (D) 的建立 全细胞和全动物模型展示了 突变 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，并希望由此带来新的、有效的 这些患者的治疗方法，但也应该提供重要的新疗法 了解角质形成细胞间的凝聚力机制， 对于所有复层鳞状上皮的完整性至关重要。