Inborn errors of cholesterol metabolism

structural lipid and a precursor molecule for bile acid and steroid hormone synthesis. In addition, this ubiquitous lipid is now known to contribute fundamentally to the development and function of the CNS and the bones, and, as detailed in other articles in this Perspective series, it plays major roles in signal transduction, sperm development, and embryonic morphogenesis. Over the past decade, the identification of multiple congenital anomaly/mental retardation syndromes due to inborn errors of cholesterol synthesis has underscored the importance of cholesterol synthesis in normal development. The prototypical example of a human malformation syndrome that results from a defect in cholesterol synthesis is the RSH/Smith-Lemli-Opitz syndrome (SLOS). To date, five additional human syndromes resulting from impaired cholesterol synthesis have been described. These include desmosterolosis, X-linked dominant chondrodysplasia punctata type 2 (CDPX2), CHILD syndrome (congenital hemidysplasia with ichthyosiform erythroderma/nevus and limb defects), Greenberg dysplasia, and, most recently, Antley-Bixler syndrome. Natural mouse mutations corresponding to CDPX2 (tattered) and CHILD syndrome (bare patches and striated) have been identified, and mouse models corresponding to SLOS and lathosterolosis have been produced by gene disruption. Identification of the biochemical defects present in these disorders has given insight into the role that cholesterol plays in normal embryonic development, has provided the initial step in understanding the pathophysiological processes underlying these malformation syndromes, and has given rise to treatment protocols for patients with SLOS. Cholesterol is synthesized from lanosterol, the first sterol in the cholesterol synthesis pathway, via a series of enzymatic reactions shown in Figure 1. These include the demethylation at C4α, C4β, and C14, which converts the C30 molecule lanosterol to C27 cholesterol; isomerization of the ∆8(9) double bond to a ∆7 double bond; desaturation to form a ∆5 double bond; and finally, reduction of ∆14, ∆24, and ∆7 double bonds (Figure 1). Analyses of human and murine syndromes resulting from cholesterol synthetic defects have helped illuminate both the normal functions of cholesterol and a range of normal and teratogenic functions of the various precursor sterols that accumulate in these disorders. Here, I consider the clinical, molecular, biochemical, and developmental aspects of these disorders, focusing on the five malformation syndromes presented in Table 1.