Sjogren-Larsson syndrome (SLS) is an inherited disorder characterized by congential ichthyosis, mental retardation and spasticity. Preliminary studies show that cultured skin fibroblasts from SLS patients have altered fatty alcohol metabolism due to deficiency of the enzyme, fatty alcohol: NAD- oxidoreductase (FAO). Normal fatty alcohol metabolism is poorly understood and no information is known about the clinical effects of altered fatty alcohol metabolism. Furthermore, human FAO has not been characterized. A long-term objective of this proposal is to understand normal fatty alcohol metabolism and how FAO deficiency may lead to the clinical phenotype of SLS. We propose to investigate fatty alcohol metabolism in cultured skin fibroblasts from normal and SLS subjects to understand the deranged fatty alcohol metabolism in SLS. Using techniques of gas-liquid chromatography in combination with radiochemical tracer studies, we will investigate the regulation of fatty alcohol levels in normal and SLS fibroblasts. FAO acitivity will be characterized in normal human fibroblasts and compared to the residual FAO activity in SLS cells to determine whether the FAO enzyme is kinetically or structurally altered. We will search for genetic heterogeneity in SLS by gene complementation analysis using the techniques of somatic cll fusion. To uderstand fatty alcohol metabolism in tissues with quite different FAO activities, metabolic studies will be performed in rat hepatocytes and brain tissue slices using radiochemnical and enzymatic techniques. The subcellualr location of enzymes involved in fatty alcohol metabolic pathways will be determined using methods of differential and density-gradient centrifugation. The pathogenesis of SLS will be investigate in rat feeding studies to establish whether tissue fatty alcohol accumulation leads to biochemical and clinical changes characteristic of SLS. These studies will provide fundamental information about normal fatty alcohol metabolism and the deranged fatty alcohol metabolism in SLS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK041843-03
Application #
3242761
Study Section
Biochemistry Study Section (BIO)
Project Start
1989-02-01
Project End
1992-01-31
Budget Start
1991-02-01
Budget End
1992-01-31
Support Year
3
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Virginia Commonwealth University
Department
Type
Schools of Medicine
DUNS #
City
Richmond
State
VA
Country
United States
Zip Code
23298
Rizzo, W B; Craft, D A; Kelson, T L et al. (1994) Prenatal diagnosis of Sjogren-Larsson syndrome using enzymatic methods. Prenat Diagn 14:577-81
Rizzo, W B; Craft, D A; Judd, L L et al. (1993) Fatty alcohol accumulation in the autosomal recessive form of rhizomelic chondrodysplasia punctata. Biochem Med Metab Biol 50:93-102
Rizzo, W B (1993) Sjogren-Larsson syndrome. Semin Dermatol 12:210-8
Zenger-Hain, J; Craft, D A; Rizzo, W B (1992) Diagnosis of inborn errors of phytanic acid oxidation using tritiated phytanic acid. Prog Clin Biol Res 375:399-407
Kelson, T L; Craft, D A; Rizzo, W B (1992) Carrier detection for Sjogren-Larsson syndrome. J Inherit Metab Dis 15:105-11
Rizzo, W B; Craft, D A (1991) Sjogren-Larsson syndrome. Deficient activity of the fatty aldehyde dehydrogenase component of fatty alcohol:NAD+ oxidoreductase in cultured fibroblasts. J Clin Invest 88:1643-8
James, P F; Rizzo, W B; Lee, J et al. (1990) Isolation and characterization of a Chinese hamster ovary cell line deficient in fatty alcohol:NAD+ oxidoreductase activity. Proc Natl Acad Sci U S A 87:6102-6