Human Molecular Genetics Advance Access originally published online on January 30, 2006
Human Molecular Genetics 2006 15(6):839-851; doi:10.1093/hmg/ddl003
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Published by Oxford University Press 2006
Development and characterization of a hypomorphic Smith–Lemli–Opitz syndrome mouse model and efficacy of simvastatin therapy
1Unit on Molecular Dysmorphology, Heritable Disorders Branch, National Institute of Child Health and Human Development, 2Veterinary Resources Program, 3Mouse Imaging Facility and 4Laboratory of Mammalian Genes and Development, National Institutes of Health, DHHS, Bethesda, MD USA, 5The Johns Hopkins University, Kennedy Krieger Institute, Baltimore, MD, USA and 6St Louis University Eye Institute, and Department of Pharmacological and Physiological Science, St Louis University School of Medicine, St Louis, MO, USA
* To whom correspondence should be addressed at: Heritable Disorders Branch, National Institute of Child Health and Human Development, National Institutes of Health, Boulevard 10, Room 9D42, 10 Center Dr., Bethesda, MD 20892, USA. Tel: +1 3014354432; Fax: +1 3014805791; Email: fdporter{at}mail.nih.gov
Received December 20, 2005; Accepted January 23, 2006
Smith–Lemli–Opitz syndrome (SLOS) is a genetic syndrome caused by mutations in the 3ß-hydroxysterol 
7-reductase gene (DHCR7). SLOS patients have decreased cholesterol and increased 7-dehydrocholesterol (7-DHC) levels. Dietary cholesterol supplementation improves systemic biochemical abnormalities; however, because of the blood–brain barrier, the central nervous system (CNS) is not treated. Simvastatin therapy has been proposed as a means to treat the CNS. Mice homozygous for a null disruption of Dhcr7, Dhcr73–5/3–5, die soon after birth, thus they cannot be used to study postnatal development or therapy. To circumvent this problem, we produced a hypomorphic SLOS mouse model by introducing a mutation corresponding to DHCR7T93M. Both Dhcr7T93M/T93M and Dhcr73–5/T93M mice are viable. Phenotypic findings in Dhcr7T93M/3–5 mice include CNS ventricular dilatation and two to three syndactyly. Biochemically, both Dhcr7T93M/T93M and Dhcr7T93M/3–5 mice have elevated tissue 7-DHC levels; however, the biochemical defect improved with age. This has not been observed in human patients, and is due to elevated Dhcr7 expression in mouse tissues. Dietary cholesterol therapy improved sterol profiles in peripheral, but not CNS tissues. However, treatment of Dhcr7T93M/3–5 mice with simvastatin decreased 7-DHC levels in both peripheral and brain tissues. Expression of Dhcr7 increased in Dhcr7T93M/3–5 tissues after simvastatin therapy, consistent with the hypothesis that simvastatin therapy improves the biochemical phenotype by increasing the expression of a Dhcr7 allele with residual enzymatic activity. We conclude that simvastatin treatment is efficacious in improving the SLOS-associated sterol abnormality found in the brain, and thus has the potential to be an effective therapeutic intervention for behavioral and learning problems associated with SLOS.