Precholesterol sterols accumulate in lipid rafts of patients with Smith-Lemli-Opitz syndrome and X-linked dominant chondrodysplasia punctata.

Abstract

Systemic fetal dysmorphogenesis in disorders of postsqualene cholesterol biosynthesis is thought to be caused by disruption of Hedgehog signaling. Because precholesterol sterols such as 7-dehydrocholesterol and lathosterol can replace cholesterol in the activation of Hedgehog proteins, it is currently believed that cholesterol deficiency-related Hedgehog signaling block occurs further downstream, probably at the level of Smoothened. Experimentally, such a block in Hedgehog signaling occurs at sterol levels of <40 mug/mg protein. Recently, we studied autopsy material from 2 infants with fatal cholesterol biosynthetic disorders (Smith-Lemli-Opitz syndrome and X-linked dominant chondrodysplasia punctata) in which the hepatic cholesterol levels were far greater. In this study, we demonstrate abnormal accumulation of sterol precursors of cholesterol in membrane lipid rafts (detergent resistance membranes) prepared from liver tissues of these 2 infants: 8-dehydrocholesterol and 7-dehydrocholesterol in lipid rafts of the infant with Smith-Lemli-Opitz syndrome and cholest-8(9)-ene-3beta-ol in lipid rafts of the infant with X-linked dominant chondrodysplasia punctata. We suggest that such alterations in the lipid raft sterol environment may affect the biology of cells and the development of fetuses with cholesterol biosynthetic disorders.

• Authors: Dinesh Rakheja, Richard L Boriack
• Journal: Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society (Pediatr Dev Pathol) 2008 Mar-Apr Vol. 11 Issue 2 Pg. 128-32 ISSN: 1093-5266 [Print] United States
• PMID: 17378665 (Publication Type: Journal Article)

Chemical References

• Cholestadienols
• Dehydrocholesterols
• cholesta-5,8-dien-3 beta-ol
• lathosterol
• Cholesterol
• 7-dehydrocholesterol

Topics

• Cholestadienols (analysis, metabolism)
• Cholesterol (analysis, biosynthesis, metabolism)
• Chondrodysplasia Punctata (genetics, metabolism, pathology)
• Dehydrocholesterols (analysis, metabolism)
• Female
• Genetic Diseases, X-Linked (genetics, metabolism, pathology)
• Humans
• Infant, Newborn
• Lipid Metabolism, Inborn Errors (genetics, metabolism, pathology)
• Liver (metabolism)
• Membrane Microdomains (chemistry, metabolism)
• Smith-Lemli-Opitz Syndrome (genetics, metabolism, pathology)
• Syndrome