Document Detail

Development and characterization of a hypomorphic Smith-Lemli-Opitz syndrome mouse model and efficacy of simvastatin therapy.
MedLine Citation:
PMID:  16446309     Owner:  NLM     Status:  MEDLINE    
Smith-Lemli-Opitz syndrome (SLOS) is a genetic syndrome caused by mutations in the 3beta-hydroxysterol Delta(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, Dhcr7(Delta3-5/Delta3-5), 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 DHCR7(T93M). Both Dhcr7(T93M/T93M) and Dhcr7(Delta3-5/T93M) mice are viable. Phenotypic findings in Dhcr7(T93M/Delta3-5) mice include CNS ventricular dilatation and two to three syndactyly. Biochemically, both Dhcr7(T93M/T93M) and Dhcr7(T93M/Delta3-5) 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 Dhcr7(T93M/Delta3-5) mice with simvastatin decreased 7-DHC levels in both peripheral and brain tissues. Expression of Dhcr7 increased in Dhcr7(T93M/Delta3-5) 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.
Lina S Correa-Cerro; Christopher A Wassif; Lisa Kratz; Georgina F Miller; Jeeva P Munasinghe; Alexander Grinberg; Steven J Fliesler; Forbes D Porter
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't     Date:  2006-01-30
Journal Detail:
Title:  Human molecular genetics     Volume:  15     ISSN:  0964-6906     ISO Abbreviation:  Hum. Mol. Genet.     Publication Date:  2006 Mar 
Date Detail:
Created Date:  2006-03-01     Completed Date:  2007-11-05     Revised Date:  2007-12-03    
Medline Journal Info:
Nlm Unique ID:  9208958     Medline TA:  Hum Mol Genet     Country:  England    
Other Details:
Languages:  eng     Pagination:  839-51     Citation Subset:  IM    
Unit on Molecular Dysmorphology, Heritable Disorders Branch, National Institute of Child Health and Human Development, Bethesda, MD 20892, USA.
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MeSH Terms
3T3 Cells
Amino Acid Substitution / genetics
Cells, Cultured
Crosses, Genetic
Disease Models, Animal*
Embryonic Stem Cells / transplantation
Magnetic Resonance Spectroscopy
Methionine / genetics
Mice, Inbred C57BL
Mutagenesis, Site-Directed
Oxidoreductases Acting on CH-CH Group Donors / genetics
Simvastatin / therapeutic use*
Smith-Lemli-Opitz Syndrome / drug therapy*,  enzymology,  genetics*
Threonine / genetics
Grant Support
Reg. No./Substance:
63-68-3/Methionine; 72-19-5/Threonine; 79902-63-9/Simvastatin; EC 1.3.-/Oxidoreductases Acting on CH-CH Group Donors; EC reductase

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