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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.

Original publication




Journal article


Annu Rev Genomics Hum Genet

Publication Date





173 - 194


Niemann–Pick disease type C, Smith–Lemli–Opitz syndrome, Tangier disease, cholesterol, sphingolipids, Abnormalities, Multiple, Antley-Bixler Syndrome Phenotype, Cholesterol, Chondrodysplasia Punctata, Genetic Diseases, X-Linked, Homeostasis, Humans, Ichthyosiform Erythroderma, Congenital, Limb Deformities, Congenital, Lipid Metabolism, Inborn Errors, Lipoproteins, LDL, Osteochondrodysplasias, Oxidoreductases Acting on CH-CH Group Donors, Steroid Metabolism, Inborn Errors