Ichthyosis in Sjogren-Larsson Syndrome

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DESCRIPTION: (Verbatim) Sjogren-Larsson syndrome (SLS) is an inherited disorder characterized by ichthyosis, mental retardation and spastic di- or tetraplegia. The disease is caused by mutations in the gene for fatty aldehyde dehydrogenase (FALDH) which result in deficient activity of this enzyme. FALDH deficiency is associated with tissue accumulation of fatty aldehyde and other lipids, which are hypothesized to cause the symptoms of SLS, but the pathogenic mechanisms are unknown. The long-term goals of our research are to understand how mutations in the FALDH gene lead to symptoms of SLS and use this knowledge to develop effective therapy. To understand the genetic mechanisms leading to deficient FALDH activity in SLS, we will characterize certain mutations in SLS patients and investigate the functional role of alternate splicing of the gene. We will investigate the pathogenesis of the cutaneous disease in SLS by characterizing the abnormal lipid metabolism in cultured skin keratinocytes and in the skin of SLS patients. To understand how fatty aldehyde interferes with normal epidermal function, we will identify fatty aldehyde-lipid and -protein adducts in SLS keratinocytes. To test the novel hypothesis that abnormal crosslinking of corneocyte proteins contributes to the ichthyosis, we will determine the extent and nature of crosslinked proteins in corneocyte cell envelopes from SLS patients. Finally, to develop an experimental animal model for studies of the biochemical pathogenesis and therapy of SLS, we will genetically engineer a FALDH gene knockout mouse and use it to characterize the biochemical response to dietary fat modification and pharmacologic therapy. These studies will provide fundamental information about the role of FALDH in epidermal lipid metabolism and promise to reveal new mechanisms for fatty aldehyde toxicity in SLS.