ICHTHYOSIS IN SJOGREN/LARSSON SYNDROME

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DESCRIPTION: (Adapted from the applicant's abstract) - The Sjogren-Larsson syndrome (SLS) is an inherited neurocutaneous disorder characterized by ichthyosis, mental retardation, and spasticity. The disease arises from mutations in the gene for fatty aldehyde dehydrogenase (FALDH) which result in deficient activity of this enzyme and accumulation of fatty alcohol in tissues. The long-term goal of the research is to understand the pathogenesis of SLS and develop effective therapy for this disease. To identify the genetic defects in SLS and uncover amino acids that are critical for catalytic activity of FALDH, the applicants will investigate the nature and distribution of mutations in a large group of unrelated SLS patients. Mutation analysis will be performed by exon screening and direct DNA sequencing. Identified mutations will be tested in a mammalian expression system to confirm that they are responsible for reduced enzyme activity. To determine whether phenotypic variation in SLS arises from genetic heterogeneity in FALDH, the applicants will correlate the clinical phenotype with the biochemical abnormalities in patients, including the residual enzymatic activity in cultured fibroblasts and keratinocytes, cellular fatty alcohol storage, fatty alcohol accumulation in plasma and erythrocytes, and, for those patients who are homozygous, the location of mutations in FALDH. To understand better the pathogenesis of SLS, they will compare the transcription and expression of FALDH in skin biopsies, cultured keratinocytes, and fibroblasts from SLS patients, and normal controls. FALDH transcripts arising from alternative splicing will be defined, their cellular location in the epidermis and relative abundance in cultured keratinocytes will be determined, and their function will be investigated using transfection assays. In addition skin equivalent cultures will be used to test the ability of cultured SLS keratinocytes to mimic the in vivo expression of FALDH and associated epidermal abnormalities. These studies will define the genetic basis for SLS and provide new understanding of the molecular and biochemical abnormalities that are responsible for cutaneous symptoms. This knowledge is critical for developing effective therapeutic approaches to this disease.