Smith-Lemli-Opitz syndrome: From cholesterol deficiency to sterol-dependent signaling dysregulation

Smith-Lemli-Opitz syndrome (SLOS) has long been considered a disorder whose primary pathogenic mechanism is cholesterol deficiency. However, accumulating evidence on the effects of the buildup of the cholesterol biosynthesis intermediate 7‑dehydrocholesterol, resulting from deficiency of the enzyme encoded by DHCR7, on membrane organization and receptor activity indicates that the pathogenic processes underlying SLOS are more complex than previously thought. Accordingly, the aim of this review is to examine SLOS not only as an inherited disorder of cholesterol biosynthesis but also as a multifactorial condition associated with alterations in the membrane organization of receptor complexes and sterol-dependent dysregulation of signaling pathways, thereby broadening current understanding of the pathogenesis of this disease.