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INTRODUCTION

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Cholesterol plays an essential role in many cellular and developmental processes. In addition to being a structural lipid in membranes and myelin, cholesterol is the precursor for bile acids, steroid hormones, neurosteroids, and oxysterol synthesis. Subcellular organelles such as caveolae and lipid rafts are enriched in cholesterol. Finally, cholesterol is necessary for the modification and the function of several hedgehog signaling proteins that control embryonic development. Most defects of cholesterol synthesis are caused by enzyme deficiencies in the post-squalene portion of the pathway (Figures 23-1 and 23-2). Only mevalonate kinase deficiency (MKD), resulting in a multisystemic (inflammatory) disorder with mevalonic aciduria (MVA) and hyperimmunoglobulinemia D syndrome (HIDS) as the extremes of a disease spectrum, is found in the proximal part of the pathway (Figure 23-3).

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FIGURE 23-1.

Pathway of post-squalene cholesterol biosynthesis. The enzymes are listed in the middle in italic. The respective genes are shown to the left in bold and italic.

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FIGURE 23-2.

Defects of the post-squalene cholesterol biosynthesis pathway. Red bars represent enzyme blocks; the corresponding disorders are given in red to the right. HEM, Greenberg dysplasia; PHA, Pelger-Huët anomaly; SC4MOL, sterol C4 methyl oxidase deficiency; CHILD, CHILD syndrome; CDPX2, Conradi-Hünermann syndrome; male EBP, hemizygous male emopamil-binding protein deficiency.

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FIGURE 23-3.

Defects of the proximal cholesterol biosynthesis pathway. The red bars represent the enzyme block; the corresponding disorders are given in red next to the bar. Accumulating metabolites are printed in blue. Metabolites that may be deficient are printed in green. MKD, mevalonate kinase deficiency; MVA, mevalonic aciduria; HIDS, hyper-IgD syndrome.

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The 27-carbon cholesterol molecule is synthesized from lanosterol, the first sterol in the cholesterol synthesis pathway, via a series of approximately 30 enzymatic reactions. Defects of cholesterol biosynthesis result in congenital malformation syndromes. Many of the malformations in Smith-Lemli-Opitz syndrome (SLOS), lathosterolosis, and desmosterolosis are consistent with impaired function of sonic hedgehog (SHH), which plays a major role in the patterning of forebrain and limb development. Mutations in the SHH gene result in holoprosencephaly, a malformation sequence also found in some patients with SLOS. Because cholesterol was thought to be essential for the autoprocessing of SHH, a splitting of the protein in an inactive part and a signaling part, the apparent dysfunction of SHH in SLOS was assumed to be caused by the interference of 7-dehydrocholesterol (7-DHC) in this process. It was later found that 7-DHC has the same effect on SHH autoprocessing as cholesterol, and it also did not impair the signaling function of sterol-modified SHH. It is now thought that decreased intracellular cholesterol levels impair the SHH signaling cascade in SLOS and lathosterolosis downstream of the SHH receptor patched at the ...

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