As reported in today's issue of The New England Journal of Medicine, scientists at the University of Pennsylvania Medical Center and the University of California at San Francisco have clarified the molecular mechanisms underlying a rare disease in which genetically male newborns -- that is, infants with both X and Y chromosomes -- are born with female external genitalia due to an inability to manufacture sex hormones. The study also provides further evidence that a protein known as StAR regulates the essential first step in the biosynthesis of all steroid hormones. These hormones are used by the body to regulate the development and activity of reproductive and other organs.
"This research advances our understanding of the molecular basis of how the sex hormones that determine our sexual phenotype and the adrenal hormones that control our responses to stress are produced," says Jerome F. Strauss III, MD, PhD, a professor of obstetrics and gynecology at Penn and coauthor on the paper.
Specifically, the scientists analyzed the genetic mutations found in patients with the rare, devastating disease called congenital lipoid adrenal hyperplasia, the most severe gene-based disorder of steroid hormone synthesis. In this disease, affected people are almost completely unable to make steroid hormones because they cannot convert cholesterol to pregnenolone, the first step in the process of steroid hormone synthesis. As a result, newborns with the XY karyotype are born with female external genitalia. In addition, the adrenal cortex of these individuals becomes engorged with cholesterol. Without treatment, the absence of steroid hormones results in severe chemical imbalances, dehydration, and death during infancy.
Earlier research by the Penn and UCSF teams had localized the defect in this disorder to mutations in the gene for the steroidogenic acute regulatory (StAR) protein. In the current study, the researchers studied the mutations found in 15 patients with divergent ethnic and genetic backgrounds to see whether different mutations are associated with different levels of severity and to try to understand how the various mutations cause the disease. Among these patients, 15 different mutations were identified. They found that while the genital manifestations of the disease are fairly consistent, the physiological clinical symptoms such as dehydration, hypertension, and wasting varied considerably. The researchers concluded that congenital lipoid adrenal hyperplasia results from two separate problems: First, mutant StAR proteins block use of cholesterol to synthesize steroid hormones and, second, the resulting accumulation of cholesterol esters and related substances damages the cells.
In a related paper that appeared in the November 26 issue of the Proceedings of the National Academy of Sciences, research associate Futoshi Arakane, MD, with Strauss and colleagues, probed further into the mechanism by which StAR stimulates conversion of cholesterol to pregnenolone. Prior studies had suggested that StAR transported cholesterol across the outer and inner mitochondrial membranes. This study showed, however, that StAR itself does not need to enter into the mitochondria for cholesterol metabolism to take place.
Together, these studies confirm that StAR plays a central role in the synthesis of steroid hormones. The specific mechanism by which StAR facilitates the conversion of cholesterol to pregnenolone remains unclear and is the object of ongoing research.
-- Dr. Jerome F. Strauss III can be reached at (215) 898-0147.
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