Correlation of severity and outcome with plasma sterol levels in variants of the Smith-Lemli-Opitz syndrome

7-Dehydrocholesterol–dependent proteolysis of HMG-CoA reductase suppresses sterol biosynthesis in a mouse model of Smith-Lemli-Opitz/RSH syndrome

“…Cholesterol and total sterol (cholesterol plus dehydrocholesterol) concentrations were significantly reduced, while levels of 7DHC and 8DHC were increased 30-to 40-fold in isolated liver microsomes, in whole liver, and in brain homogenates from Dhcr7 -/-newborn mice (Table 1). Except for 8DHC/7DHC ratios that were lower than those noted in humans (16,20), sterol compositions in Dhcr7 -/-mice closely resembled that in SLOS. Cholesterol deficits in homozygous mice were most profound in the brain with dehydrocholesterols making up 80% of total sterols.…”

“…Cholesterol plays an essential role in development because it is needed to activate the morphogenic sonic hedgehog (SHH) signal pathway during early gestation (19), and adverse effects of cholesterol deprivation in the prenatal period are amply illustrated in SLOS by the strong inverse dependence of symptom severity and perinatal mortality on plasma cholesterol levels (8,20). In contrast to cholesterol, 7DHC fails to stimulate the SHH pathway (21).…”

Inability to fully suppress sterol synthesis rates with exogenous sterol in embryonic and extraembyronic fetal tissues

“…The deficiency of cholesterol can lead to a wide range of congenital defects, ranging from the mild (minor physical abnormality with behavioral and learning disabilities) to the severe (lethal with multiple major congenital anomalies) [6,7]. Not surprising, the severity of the syndrome is correlated with circulating sterol concentrations [8].…”

Conversion of 7-Dehydrocholesterol to 7-Ketocholesterol Is Catalyzed by Human Cytochrome P450 7A1 and Occurs by Direct Oxidation without an Epoxide Intermediate

“…Thus, 7-dehydrocholesterol is important aside from its reduction to cholesterol. Some humans are deficient in 7-dehydrocholesterol reductase (DHCR7) and exhibit Smith-Lemli-Opitz syndrome (SLOS), 2 with elevated levels of 7-dehydrocholesterol and attenuated levels of cholesterol (3,(7)(8)(9)(10). 7-Dehydrocholesterol is exceptionally susceptible to free radical oxidation (11), and more than one dozen biologically active oxysterol products have been characterized from 7-dehydrocholesterol oxidation in solution (12)(13)(14).…”