++
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).
++++++++
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 level of smoothened, a G-protein-linked protein.
++...