S. Shefer et al., MARKEDLY INHIBITED 7-DEHYDROCHOLESTEROL-DELTA(7)-REDUCTASE ACTIVITY IN LIVER-MICROSOMES FROM SMITH-LEMLI-OPITZ HOMOZYGOTES, The Journal of clinical investigation, 96(4), 1995, pp. 1779-1785
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.