title: Residual cholesterol synthesis and simvastatin induction of cholesterol synthesis in Smith-Lemli-Opitz syndrome fibroblasts.
abstract: Smith-Lemli-Opitz syndrome (RSH/SLOS) is an autosomal recessive, malformation syndrome caused by mutations in the 3beta-hydroxysterol delta7-reductase gene (DHCR7). DHCR7 catalyzes the reduction of 7-dehydrocholesterol (7DHC) to cholesterol. We report the mutation analysis and determination of residual cholesterol synthesis in 47 SLOS patients, and the effects of treatment of SLOS skin fibroblasts with simvastatin. Using deuterium labeling we have quantified the amount of synthesized cholesterol and 7DHC in homozygote, heterozygote, and control fibroblast cell lines. In SLOS fibroblasts, the fraction of synthesized cholesterol to total sterol synthesis ranged from undetectable to over 50%. This establishes that different mutant alleles encode enzymes with varying degrees of residual activity. There was a correlation between increased phenotypic severity and decreased residual cholesterol synthesis (r(2)=0.45, p<0.0001). Simvastatin treatment of SLOS fibroblasts with residual DHCR7 enzymatic activity decreased 7DHC levels and increased cholesterol synthesis. This increase in cholesterol synthesis is due to increased expression of a mutant allele with residual function. Determination of residual enzymatic activity for specific DHCR7 mutant alleles will help in understanding the processes underlying the broad phenotypic spectrum found in this disorder and will be useful in identifying patients who may benefit from simvastatin therapy.
authors.affiliation: Heritable Disorders Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Wassif
authors.forename: Patrycja A
authors.initials: PA
authors.lastname: Krakowiak
authors.forename: Brooke S
authors.initials: BS
authors.lastname: Wright
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Gewandter
authors.forename: Allison L
authors.initials: AL
authors.lastname: Sterner
authors.forename: Norman
authors.initials: N
authors.lastname: Javitt
authors.forename: Alfred L
authors.initials: AL
authors.lastname: Yergey
authors.forename: Forbes D
authors.initials: FD
authors.lastname: Porter
mesh_terms: D000483:Alleles; D002460:Cell Line; D002784:Cholesterol / Q000096:biosynthesis*; D003684:Dehydrocholesterols / Q000037:antagonists & inhibitors; D005347:Fibroblasts / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D005838:Genotype; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D009154:Mutation; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000235:genetics / Q000378:metabolism*; D019821:Simvastatin / Q000494:pharmacology*; D012867:Skin / Q000473:pathology; D019082:Smith-Lemli-Opitz Syndrome / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology
chemical_list: D003684:Dehydrocholesterols; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D002784:Cholesterol; D019821:Simvastatin; C016705:7-dehydrocholesterol; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019995:7-dehydrocholesterol reductase