Epidermolysis bullosa simplex are a group of inherited disorders characterized primarily by nonscarring intraepidermal blisters that result from lysis of basal cells induced by mechanical trauma. For 3 of the clinical variants, the molecular basis of the skin fragility has been identified as mutations in either one of the basal cell-specific keratins. Keratins 5 and 14 form obligate heterodimers, which assemble in a series of higher ordered interactions to construct the 10 nm keratin intermediate filament. Missense mutations in either keratin 5 or 14 that interfere with molecular assembly or structure result in an abnormal keratin cytoskeletal network and cell fragility. Defects in novel proteins, which either interact with the keratin cytoskeleton, modify the filaments, or mediate filament attachment to cellular components, such as the nuclear envelope, hemidesmosome, desmosome, or other structures, may underlie other disorders of skin fragility. Towards the goals of understanding the normal structure and function of the keratin cytoskeleton, how different mutations in keratin interfere with cytoskeletal assembly and function, and if genomic imprinting influences the incidence of new mutations in keratin genes, we propose to accomplish the following specific aims: 1. To identify and characterize proteins that interact with keratins. 2. To determine if new keratin gene mutations preferentially occur on the paternal or maternal allele. 3. To determine if keratin gene defects underlie either bullous diseases with unusual clinical presentation or other selected disorders of keratinization. 4. To identify and collect patients with an unusual presentation of bullous disease and/or other genetic disorder that may result from defects in-associated proteins. This work may provide new insight into the structure and function of the keratin cytoskeleton, identify novel proteins important in normal keratinocyte function and differentiation, and identify new mutations underlying bullous disorders.
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