The involvement of 3 beta-hydroxysterol-delta(sup 24)-reductase, a post-squalene enzyme in cholesterol biosynthesis, in desmosterolosis

Abstract

As a structural component of mammalian cell membranes, cholesterol is essential for increasing the rigidity of the lipid bilayer and thus decreasing membrane fluidity and permeability. Cholesterol or its precursors are also essential for the synthesis of a wide variety of molecules that affect diverse physiological functions including nutrient absorption, vitamin balance, stress responses, reproductive function and osmoregulation. Hence, an elaborate regulatory system involving more than 100 genes has evolved to maintain the concentration of cholesterol within narrow limits. During the past 10 years, a number of defects in the late stages of the biosynthetic pathway have been associated with diseases. These diseases are linked with the accumulation of a variety of intermediate precursors which will in many cases at least partially compensate for the associated hypocholesterolemia. One such condition is desmosterolosis, an autosomal recessive disorder which results from mutations in the 3 beta-hydroxysterol-Delta(sup 24)-reductase gene. The associated pathology underscores the essential roles of cholesterol not only in the maintenance of normal cell functioning but also during ontogeny. The discovery of this and other post-squalene genetic disorders provides a new tool to better understand the essential roles of cholesterol in homeostasis.