Sjögren-Larsson syndrome (SLS) is an inherited disorder associated with impaired
fatty alcohol oxidation due to deficient activity of
fatty alcohol:NAD+ oxidoreductase (FAO). FAO is a complex
enzyme which consists of two separate
proteins that sequentially catalyze the oxidation of
fatty alcohol to
fatty aldehyde and
fatty acid. To determine which enzymatic component of FAO was deficient in SLS, we assayed
fatty aldehyde dehydrogenase (FALDH) and
fatty alcohol dehydrogenase in cultured fibroblasts from seven unrelated SLS patients. All SLS cells were selectively deficient in the FALDH component of FAO, and had normal activity of
fatty alcohol dehydrogenase. The extent of
FALDH deficiency in SLS cells depended on the aliphatic
aldehyde used as substrate, ranging from 62% of mean normal activity using
propionaldehyde as substrate to 8% of mean normal activity with octadecanal. FALDH activity in obligate SLS heterozygotes was partially decreased to 49 +/- 7% of mean normal activity using octadecanal as substrate. Differential centrifugation studies in fibroblasts indicated that this FALDH
enzyme was largely particulate; soluble FALDH activity was normal in SLS cells. Intact SLS fibroblasts oxidized octadecanol to
fatty acid at less than 10% of the normal rate, but oxidized free octadecanal normally, suggesting that the FALDH affected in SLS is chiefly involved in the oxidation of
fatty alcohol to
fatty acid. These results show that the primary enzymatic defect in SLS is the FALDH component of the FAO complex, which leads to deficient oxidation of
fatty aldehyde derived from
fatty alcohol.