MARKEDLY INHIBITED 7-DEHYDROCHOLESTEROL-DELTA(7)-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 cholest erol with increased 7-dehydrocholesterol concentrations are biochemica l features diagnostic of the inherited enzyme defect, Using isotope in corporation assays, we measured the transformation of the precursors, [3 alpha-H-3]lathosterol and [1,2-H-3]7-dehydrocholesterol into choles terol by liver microsomes from seven controls and four Smith-Lemli-Opi tz homozygous subjects, The introduction of the double bond in lathost erol at C-5[6] to form 7-dehydrocholesterol that is catalyzed by latho sterol-5-dehydrogenase was equally rapid in controls and homozygotes l iver 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-dehydr ocholesterol to yield cholesterol catalyzed by 7-dehydrocholesterol-De lta(7)-reductase was nine times greater in controls than homozygotes m icrosomes (365+/-23 vs 40+/-4 pmol/mg protein per min, P < 0.0001), Th ese results demonstrate that the pathway of lathosterol to cholesterol in human liver includes 7-dehydrocholesterol as a key intermediate, I n Smith-Lemli-Opitz homozygotes, the transformation of 7-dehydrocholes terol to cholesterol by hepatic microsomes was blocked although 7-dehy drocholesterol was produced abundantly from lathosterol, Thus, lathost erol 5-dehydrogenase is equally active which indicates that homozygote s liver microsomes are viable, Accordingly, microsomal 7-dehydrocholes terol-Delta(7)-reductase is inherited abnormally in Smith-Lemli-Opitz homozygotes.