Smith-Lemli-Opitz syndrome (SLOS) is a hereditary disorder in which a defective gene encoding 7-dehydrocholesterol reductase causes the accumulation of noncholesterol sterols, such as 7- and 8-dehydrocholesterol. Using rigorous analytical methods in conjunction with a large collection of authentic standards, we unequivocally identified numerous noncholesterol sterols in 6 normal and 17 SLOS blood samples. Plasma or erythrocytes were saponified under oxygen-free conditions, followed by multiple chromatographic separations. Individual sterols were identified and quantitated by high performance liquid chromatography (HPLC), Ag+-HPLC, gas chromatography (GC), GC-mass spectrometry, and nuclear magnetic resonance. As a percentage of total sterol content, the major C27 sterols observed in the SLOS blood samples were cholesterol (12-98%), 7-dehydrocholesterol (0.4-44%), 8-dehydrocholesterol (0.5-22%), and cholesta-5,7,9(11)-trien-3β-ol (0.02-5%), whereas the normal blood samples contained <0.03% each of the three noncholesterol sterols. SLOS and normal blood contained similar amounts of lathosterol (0.05-0.6%) and cholestanol (0.1-0.4%) and ∼0.003-0.1% each of the Δ8, Δ8(14), Δ5,8(14), Δ5,24, Δ6,8, Δ6,8(14), and Δ7,24 sterols. The results are consistent with the hypothesis that the Δ8(14) sterol is an intermediate of cholesterol synthesis and indicate the existence of undescribed aberrant pathways that may explain the formation of the Δ5,7,9(11) sterol. 19-Norcholesta-5,7,9-trien-3β-ol was absent in both SLOS and normal blood, although it was routinely observed as a GC artifact in fractions containing 8-dehydrocholesterol. The overall findings advance the understanding of SLOS and provide a methodological model for studying other metabolic disorders of cholesterol synthesis.
|Original language||English (US)|
|Number of pages||14|
|Journal||Journal of Lipid Research|
|State||Published - 2001|
- Noncholesterol sterols
ASJC Scopus subject areas
- Cell Biology