Lowered DHCR7 activity measured by ergosterol conversion in multiple cell types in Smith–Lemli–Opitz syndrome

Smith–Lemli–Opitz syndrome (SLOS) is an autosomal recessive disorder of cholesterol metabolism characterized by multiple congenital anomalies and mental retardation. SLOS results from mutations in 7-dehydrocholesterol Δ 7 reductase ( DHCR7), the gene encoding the final enzyme involved in cholesterol biosynthesis. The resulting cholesterol deficiency and excessive 7- and 8-dehydrocholesterol (7-DHC, 8-DHC) in plasma and tissues are almost always diagnostic for SLOS. We measured DHCR7 activity in fibroblasts, amniocytes, and chorionic villi from controls, heterozygotes, and SLOS subjects. The enzyme activity (expressed as percent conversion of substrate) was significantly lower in untransformed fibroblasts from SLOS subjects (4.47% ± 0.72) compared to untransformed fibroblasts from heterozygotes (26.6% ± 4.6, p < 0.01) or controls (50.6% ± 5.3, p < 0.001). We also measured plasma cholesterol and 7-DHC, determined the severity score and identified DHCR7 mutations for most of the subjects. There was no significant correlation of enzyme activity with severity score, plasma cholesterol level, plasma 7-DHC level, or the 7-DHC:cholesterol ratio. We conclude that even though enzyme activity as measured by the ergosterol assay may not correlate with severity, this assay has the potential to distinguish SLOS cells from carrier or unaffected cells in a variety of cell types, and should prove useful in confirming a diagnosis in atypical cases where sterol levels are equivocal. Additionally, it may be important to measure residual enzyme activity in SLOS subjects being considered for a trial of statins, as this treatment could theoretically be detrimental in subjects with little or no DHCR7 activity. Finally, the data suggest a threshold enzyme activity of 8% conversion, below which disease occurs.