title: Disorders of cholesterol metabolism and their unanticipated convergent mechanisms of disease.
abstract: Cholesterol plays a key role in many cellular processes, and is generated by cells through de novo biosynthesis or acquired from exogenous sources through the uptake of low-density lipoproteins. Cholesterol biosynthesis is a complex, multienzyme-catalyzed pathway involving a series of sequentially acting enzymes. Inherited defects in genes encoding cholesterol biosynthetic enzymes or other regulators of cholesterol homeostasis result in severe metabolic diseases, many of which are rare in the general population and currently without effective therapy. Historically, these diseases have been viewed as discrete disorders, each with its own genetic cause and distinct pathogenic cascades that lead to its specific clinical features. However, studies have recently shown that three of these diseases have an unanticipated mechanistic convergence. This surprising finding is not only shedding light on details of cellular cholesterol homeostasis but also suggesting novel approaches to therapy.
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford OX1 3QT, United Kingdom; email: frances.platt@pharm.ox.ac.uk.
authors.forename: Frances M
authors.initials: FM
authors.lastname: Platt
authors.forename: Christopher
authors.initials: C
authors.lastname: Wassif
authors.forename: Alexandria
authors.initials: A
authors.lastname: Colaco
authors.forename: Andrea
authors.initials: A
authors.lastname: Dardis
authors.forename: Emyr
authors.initials: E
authors.lastname: Lloyd-Evans
authors.forename: Bruno
authors.initials: B
authors.lastname: Bembi
authors.forename: Forbes D
authors.initials: FD
authors.lastname: Porter
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics / Q000473:pathology; D054882:Antley-Bixler Syndrome Phenotype / Q000235:genetics / Q000473:pathology; D002784:Cholesterol / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D002806:Chondrodysplasia Punctata / Q000235:genetics / Q000473:pathology; D040181:Genetic Diseases, X-Linked / Q000235:genetics / Q000473:pathology; D006706:Homeostasis; D006801:Humans; D016113:Ichthyosiform Erythroderma, Congenital / Q000235:genetics / Q000473:pathology; D017880:Limb Deformities, Congenital / Q000235:genetics / Q000473:pathology; D008052:Lipid Metabolism, Inborn Errors / Q000235:genetics / Q000473:pathology; D008077:Lipoproteins, LDL / Q000235:genetics / Q000378:metabolism*; D010009:Osteochondrodysplasias / Q000235:genetics / Q000473:pathology; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000172:deficiency / Q000235:genetics; D043202:Steroid Metabolism, Inborn Errors / Q000235:genetics / Q000473:pathology
chemical_list: D008077:Lipoproteins, LDL; D002784:Cholesterol; D044925:Oxidoreductases Acting on CH-CH Group Donors
keywords: Niemann–Pick disease type C; Smith–Lemli–Opitz syndrome; Tangier disease; cholesterol; sphingolipids