MOLECULAR GENETICS OF HAILEY HAILEY DISEASE

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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.