Smith-Lemli-Opitz syndrome (SLOS) is a dysmorphology and mental retardation disorder lacking adequate therapy options. It is caused by cholesterol deficiency due to inactivity of 7-dehydrocholesterol-A7-reductase (DHCR7). Biochemically, it is characterized by low concentrations of cholesterol (C) in blood and tissues and high concentrations of dehydrbcholesterol (DHC). Although mutations in the DHCR7 gene have been well described, the pathogenic development of the disease characteristics is not well understood. Among inherited errors of metabolism, SLOS is relatively frequent, and new diagnostic methods aid its prenatal detection. The long-term objective of this proposal is to develop a basis for the treatment of SLOS. For experiments, mouse models that closely mimic human SLOS will be used.
Three Specific Aims are proposed:
(Aim1) Identify and quantify biochemical markers of SLOS. Using highly sensitive mass spectrometric methods, sterols and steroids will be measured in serum, urine and tissues of mutant and control mice. Ratios of DHC/C and dehydro steroids/normal analogs will provide markers for evaluating mutant severity, biochemical changes during development and effects of treatments. Because major characteristics of SLOS include neurological problems, special attention is given to neurosteroids.
(Aim 2) Normalize cholesterol levels in adults and newborns. The effects of dietary cholesterol and gene transfer will be evaluated using the biochemical markers. Gene transfer experiments will utilize viral vectors to deliver a functional DHCR7 gene to the mutant mice. Because SLOS is both a developmental problem and a continuing problem perpetuated by deficient cholesterol metabolism, mice will be treated at different developmental stages. This will help establish the time line of pathogenesis and aid distinguishing between irreversible (untreatable) and reversible (treatable) SLOS characteristics.
(Aim 3) Correct cholesterol levels during fetal development. Here the emphasis is on preventive treatment and establishing when during development irreversible damage occurs. Both biochemical markers and dysmorphic features will be monitored. Later tests for all three Specific Aims will explore neuromuscular and behavioral performance to see if they are correlated with changes in the biochemical markers. Long-term consequences, safety and potential adverse effects of treatment will also be monitored. Because of the multiple essential roles of cholesterol, SLOS is a complicated and devastating disease in spite of its relatively simple genetic origin. The frequency of SLOS in North America is estimated to be in the range of 1 in 20,000 to 30,000, although many cases are thought to be never diagnosed. Through the proposed experiments using SLOS mice, we hope to learn more about the timing and biochemistry of disease development and to establish a basis for eventual treatment in humans.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD053036-03
Application #
7347021
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Oster-Granite, Mary Lou
Project Start
2006-04-15
Project End
2011-02-28
Budget Start
2008-03-01
Budget End
2009-02-28
Support Year
3
Fiscal Year
2008
Total Cost
$265,111
Indirect Cost
Name
Children's Hospital & Res Ctr at Oakland
Department
Type
DUNS #
076536184
City
Oakland
State
CA
Country
United States
Zip Code
94609
Makarova, Anastasia M; Pasta, Saloni; Watson, Gordon et al. (2017) Attenuation of UVR-induced vitamin D3 synthesis in a mouse model deleted for keratinocyte lathosterol 5-desaturase. J Steroid Biochem Mol Biol 171:187-194
Pasta, Saloni; Akhile, Omoye; Tabron, Dorothy et al. (2015) Delivery of the 7-dehydrocholesterol reductase gene to the central nervous system using adeno-associated virus vector in a mouse model of Smith-Lemli-Opitz Syndrome. Mol Genet Metab Rep 4:92-98
Ying, Lee; Matabosch, Xavier; Serra, Montserrat et al. (2014) Biochemical and Physiological Improvement in a Mouse Model of Smith-Lemli-Opitz Syndrome (SLOS) Following Gene Transfer with AAV Vectors. Mol Genet Metab Rep 1:103-113
Meljon, Anna; Watson, Gordon L; Wang, Yuqin et al. (2013) Analysis by liquid chromatography-mass spectrometry of sterols and oxysterols in brain of the newborn Dhcr7(?3-5/T93M) mouse: a model of Smith-Lemli-Opitz syndrome. Biochem Pharmacol 86:43-55
Meljon, Anna; Theofilopoulos, Spyridon; Shackleton, Cedric H L et al. (2012) Analysis of bioactive oxysterols in newborn mouse brain by LC/MS. J Lipid Res 53:2469-83
Shackleton, Cedric H L (2012) Role of a disordered steroid metabolome in the elucidation of sterol and steroid biosynthesis. Lipids 47:1-12
Matabosch, Xavier; Ying, Lee; Serra, Montserrat et al. (2010) Increasing cholesterol synthesis in 7-dehydrosterol reductase (DHCR7) deficient mouse models through gene transfer. J Steroid Biochem Mol Biol 122:303-9
Serra, Montserrat; Matabosch, Xavier; Ying, Lee et al. (2010) Hair and skin sterols in normal mice and those with deficient dehydrosterol reductase (DHCR7), the enzyme associated with Smith-Lemli-Opitz syndrome. J Steroid Biochem Mol Biol 122:318-25
Matabosch, Xavier; Rahman, Mahbuba; Hughes, Beverly et al. (2009) Steroid production and excretion by the pregnant mouse, particularly in relation to pregnancies with fetuses deficient in Delta7-sterol reductase (Dhcr7), the enzyme associated with Smith-Lemli-Opitz syndrome. J Steroid Biochem Mol Biol 116:61-70
Griffiths, William J; Wang, Yuqin; Karu, Kersti et al. (2008) Potential of sterol analysis by liquid chromatography-tandem mass spectrometry for the prenatal diagnosis of Smith-Lemli-Opitz syndrome. Clin Chem 54:1317-24

Showing the most recent 10 out of 11 publications