Identification of scavenger receptor BI as a potential screening candidate for congenital primary adrenal insufficiency in humans

Abstract

Glucocorticoids belong to the superfamily of steroid hormones that are synthesized from the common precursor cholesterol. Adrenal gland-derived glucocorticoids, e.g., cortisol in humans and corticosterone in rodents, contribute to various processes essential for normal daily life. Glucocorticoid deficiency, also referred to as primary adrenal insufficiency, therefore, often becomes evident early in life and can be present with hypoglycemia, a failure to thrive, recurrent development of infections, and neurological problems, such as seizures and coma. The majority of congenital primary adrenal insufficiency cases are caused by deleterious mutations in genes involved in the intracellular mobilization of cholesterol and the subsequent conversion of cholesterol into glucocorticoids. A significant number of glucocorticoid deficiency cases, however, cannot be explained by known genetic variations. This perspective highlights existing literature regarding the importance of lipoprotein-derived cholesterol acquisition through scavenger receptor class B, type I (SR-BI/SCARB1) for the maintenance of an optimal adrenal glucocorticoid function in mice and humans. On the basis of the reviewed findings, it is suggested that the SCARB1 gene should be included in the standard glucocorticoid deficiency genetic screening panel to 1) facilitate knowledge development on the relative contribution of SR-BI-mediated cholesterol acquisition to steroid hormone synthesis in humans and 2) open up the possibility to reclassify glucocorticoid deficiency patients without a currently known genetic cause for concomitant treatment optimization.