Markedly inhibited 7-dehydrocholesterol-Δ⁷-reductase activity in liver microsomes from Smith-Lemli-Opitz homozygotes

We investigated the enzyme defect in late cholesterol biosynthesis in the Smith-Lemli-Opitz syndrome, a recessively inherited developmental disorder characterized by facial dysmorphism, mental retardation, and multiple organ congenital anomalies. Reduced plasma and tissue cholesterol with increased 7- dehydrocholesterol concentrations are biochemical features diagnostic of the inherited enzyme defect. Using isotope incorporation assays, we measured the transformation of the precursors, [3α-³H]lathosterol and [1,2³H]7- dehydrocholesterol into cholesterol by liver microsomes from seven controls and four Smith-Lemli-Opitz homozygous subjects. The introduction of the double bond in lathosterol at C-5[6] to farm 7-dehydrocholesterol that is catalyzed by lathosterol-5-dehydrogenase was equally rapid in controls and homozygotes liver microsomes (120±8 vs 100±7 pmol/mg protein per min, P = NS). In distinction, the reduction of the double bond at C-7 [8] in 7- dehydrocholesterol to yield cholesterol catalyzed by 7-dehydro- cholesterolΔ⁷-reductase was nine times greater in controls than homozygotes microsomes (365±23 vs 40±4 pmol/mg protein per rain, P < 0.0001). These results demonstrate that the pathway of lathosterol to cholesterol in human liver includes 7-dehydrocholesterol as a key intermediate. In Smith-Lemli- Opitz hemozygotes, the transformation of 7-dehydrocholesterol to cholesterol by hepatic microsomes was blocked although 7-dehydrocholesterol was produced abundantly from lathosterol. Thus, lathosterol 5-dehydrogenase is equally active which indicates that homozygotes liver microsomes are viable. Accordingly, microsomal 7-dehydrocholesterol-Δ⁷-reductase is inherited abnormally in Smith-Lemli-Opitz homozygotes.