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 3β-hydroxysterol Δ 7 -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 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.