Precholesterol sterols accumulate in lipid rafts of patients with Smith-Lemli-Opitz Syndrome and X-linked dominant Chondrodysplasia punctata

Dinesh Rakheja, Richard L. Boriack

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Systemic fetal dysmorphogenesis in disorders of post-squalene 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 μg/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-3β-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.

Original languageEnglish (US)
Pages (from-to)128-132
Number of pages5
JournalPediatric and Developmental Pathology
Volume11
Issue number2
DOIs
StatePublished - Mar 2008

Fingerprint

Chondrodysplasia Punctata
Smith-Lemli-Opitz Syndrome
Sterols
Cholesterol
Lipids
Hedgehog Proteins
Squalene
Liver
Membrane Lipids
Detergents
Cell Biology
Autopsy
Fetus
Membranes

Keywords

  • Lipid rafts
  • Postsqualene cholesterol biosynthetic disorders
  • Smith-Lemli-Opitz syndrome
  • X-linked dominant chondrodysplasia punctata

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Pathology and Forensic Medicine

Cite this

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title = "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 post-squalene 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 μg/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-3β-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.",
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