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

Smith-Lemli-Opitz/RSH syndrome (SLOS), a relatively common birth-defect men tal-retardation syndrome, is caused by mutations in DHCR7, whose product ca talyzes an obligate step in cholesterol biosynthesis, the conversion of 7-d ehydrocholesterol to cholesterol. A null mutation in the murine Dhcr7 cause s an identical biochemical defect to that seen in SLOS, including markedly reduced tissue cholesterol and total sterol levels, and 30- to 40-fold elev ated concentrations of 7-dehydrocholesterol. Prenatal lethality was not not ed, but newborn homozygotes breathed with difficulty, did not suckle, and d ied soon after birth with immature lungs, enlarged bladders, and, frequentl y, cleft palates. Despite reduced sterol concentrations in Dhcr7(-/-) mice, mRNA levels for 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-controlling enzyme for sterol biosynthesis, the LDL receptor, and SREBP-2 appeared neither elevated nor repressed. In contrast to mRNA, prot ein levels and activities of HMG-CoA reductase were markedly reduced. Consi stent with this finding, 7-dehydrocholesterol accelerates proteolysis of HM G-CoA reductase while sparing other key proteins. These results demonstrate that :in mice without Dhcr7 activity, accumulated 7-dehydrocholesterol sup presses sterol biosynthesis posttranslationally. This effect might exacerba te abnormal development in SLOS by increasing the fetal cholesterol deficie ncy.