title: Loss of apolipoprotein E exacerbates the neonatal lethality of the Smith-Lemli-Opitz syndrome mouse.
abstract: The Smith-Lemli-Opitz syndrome (SLOS) is caused by a genetic defect in cholesterol biosynthesis; mutations in the enzyme 3ss-hydroxysterol Delta7 reductase (Dhcr7) lead to a failure of cholesterol (and desmosterol) synthesis, with an accumulation of precursor sterols, such as 7-dehydrocholesterol. Extensive genotype-phenotype analyses have indicated that there is considerable variation in the severity of the disease, much of which is not explained by defects in the Dhcr7 gene alone. Factors ranging from variations in maternal-fetal cholesterol transfer during pregnancy, to other genetic factors have been proposed to account for this variability. Variations at the APOE locus affect plasma cholesterol levels in humans and this polymorphic gene has been found to be associated with cardiovascular as well as neurological disorders. This locus has recently been implicated in accounting for some of the variations in SLOS. To address whether maternal hypercholesterolemia can affect fetal outcome, we tested the ability of maternal hypercholesterolemia to rescue the neonatal lethality in a mouse model of SLOS. Maternal hypercholesterolemia, induced by ApoE or Ldl-r deficiency not only failed to ameliorate the postnatal lethality, it increased the prenatal mortality of Dhcr7 deficient pups. Thus the murine data suggest that maternal loss of ApoE or Ldl-r function further exacerbates the neonatal lethality, suggesting they may play a role in maternal transfer of cholesterol to the embryo.
authors.affiliation: Division of Endocrinology, Metabolism and Clinical Nutrition, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Curzio
authors.initials: C
authors.lastname: Solcà
authors.forename: Bhaswati
authors.initials: B
authors.lastname: Pandit
authors.forename: Hongwei
authors.initials: H
authors.lastname: Yu
authors.forename: G Stephen
authors.initials: GS
authors.lastname: Tint
authors.forename: Shailendra B
authors.initials: SB
authors.lastname: Patel
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001057:Apolipoproteins E / Q000235:genetics*; D001921:Brain / Q000378:metabolism; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D004622:Embryo, Mammalian / Q000378:metabolism; D005260:Female; D005804:Genes, Lethal; D005838:Genotype; D006801:Humans; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011247:Pregnancy; D019082:Smith-Lemli-Opitz Syndrome / Q000097:blood / Q000235:genetics* / Q000378:metabolism*; D014280:Triglycerides / Q000097:blood / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D014280:Triglycerides; D002784:Cholesterol