Editors' ChoiceMendelian Disease

Getting to the Root of SLOS

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Science Translational Medicine  11 Jul 2012:
Vol. 4, Issue 142, pp. 142ec122
DOI: 10.1126/scitranslmed.3004563

Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive Mendelian disorder caused by defects in cholesterol biosynthesis that results in a variety of symptoms, including microcephaly, facial dysmorphism, and cardiac and genitourinary anomalies. The disease is caused by mutations in the gene encoding 7-dehydrocholesterol reductase (DHCR7) that lead to a deficiency in delta-7-sterol reductase, the enzyme that converts 7-dehydrocholesterol (7-DHC) to cholesterol. The diagnostic biochemical characteristic is an increase in 7-DHC, but with cholesterol levels remaining low to normal. Given that 7-DHC is susceptible to attack by reactive oxygen species—leading to the formation of lipid peroxidation products, including oxysterols—Korade et al. set out to test whether systemic oxidative stress could contribute to SLOS.

The authors used a genetic mouse model of SLOS in which the gene encoding delta-7-sterol reductase was deleted. They demonstrate that a number of different oxysterol species accumulate in the brain and liver of these mice but not in wild-type animals. The authors predicted that these oxysterols—DHCEO, 4α- and 4β-hydroxy-7-DHC, as well as 24-hydroxy-7-DHC—might accrue endogenously because of oxidation of 7-DHC, which is an abundant lipid in the SLOS mouse model. The researchers confirmed these findings in rats in which the action of delta-7-sterol reductase was pharmacologically inhibited. Despite overall lower tissue concentrations of fatty acids in the SLOS mice, the authors found increased neuroprostane formation, indicating endogenous nonenzymatic peroxidation of docosahexanoic acid, which is an indicator of oxidative stress. The authors conclude that increased oxidative stress may contribute to the biochemical changes observed in SLOS. Study of genetic and pharmacological animal models of SLOS together with patients suffering from this syndrome should provide a better understanding of the pathogenesis of SLOS and the potential of antioxidants for treating this disorder.

Z. Korade et al., Lipid biomarkers of oxidative stress in a genetic mouse model of Smith-Lemli-Opitz syndrome. J. Inherit. Metab. Dis., 21 June 2012 (10.1007/s10545-012-9504-z). [PubMed]

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