Smith-Lemli-Opitz syndrome (RSH/SLOS) is an autosomal recessive, malformation syndrome caused by mutations in the 3b-hydroxysterol D 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 < 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. Published by Elsevier Inc.

A B S T R A C T The excretion of coproporphyrin isomers I and III was studied in the rat. Both isomers were found to bind equally to rat plasma and liver cytosol in vitro and to disappear from plasma at equal rates after single injections in vivo. During equimolar infusions of isomers into bile fistula animals, both the I and III isomers were excreted in bile in a concentration ratio of 2: 1, respectively. Pretreatment of animals with ethinylestradiol or simultaneous infusions of phenoldibromophthalein disulfonate caused a reduction in total hepatic excretion with no change in the 2: 1 ratio in bile. As hepatic excretion fell, excretion of both isomers in urine rose, with an increase in the proportion of the I isomer. The findings mimic those reported to occur in man and can be explained by inhibition of a common carrier which requires a stereospecific configuration that statistically favors the hepatic transport of the symmetrical coproporphyrin I isomer.

The toxic role of 7-ketocholesterol and existing pathways for its neutralization may point the way to a unified theory that explains the cause of age-related macular degeneration and points towards novel therapeutic interventions.

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