Corticosteroid-binding globulin (CBG) is the principal carrier for glucocorticoids in the circulation and a regulator of their bioavailability. Inherited CBG deficiencies are rarely reported, and only three causative mutations in four families have been described. Patients, Methods, and Results: In a 26-yr-old female with hypotension, fatigue, and undetectable total serum cortisol at presentation, we have identified a novel homozygous c.776gϾt transversion in exon 3 of the CBG (SERPINA6) gene.

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... his results in a p.Gly237Val substitution that is predicted to influence the positioning of two ␤-sheets that constitute part of the CBG steroid-binding site. Two siblings were also homozygous for the variant, whereas her mother and an unaffected sibling were heterozygous. No other symptomatic family members were identified apart from the proband. Individuals homozygous for the variant had serum CBG levels below the reference range when measured by RIA, but CBG was unmeasurable in cortisol-binding capacity assays. In the same individuals, we observed very low baseline and stimulated total serum cortisol levels but normal free serum and salivary cortisol and plasma ACTH. In a study of ultradian cortisol pulsatility, increased pulse frequency was only observed in the proband. Conclusion: We describe a novel CBG variant that lacks steroid binding activity. All mutant homozygotes have very low total serum cortisol, but normal free serum cortisol levels. The only biochemical feature to distinguish the symptomatic subject was increased cortisol pulsatility, and we suggest that this may influence glucocorticoid signaling and contribute to symptoms previously associated with CBG deficiency. (J Clin Endocrinol Metab 95: E142-E150, 2010) C orticosteroid-binding globulin (CBG) is the main transport protein for glucocorticoids in blood. Plasma CBG is produced by the liver as a 50-to 60-kDa glycoprotein with a single steroid-binding site, and its affinity (0.5 nM) for glucocorticoids is at least four orders of magnitude higher than that of albumin (1). As a result, approximately 80% of cortisol binds to CBG in human plasma, whereas 10 -15% binds to albumin and only approximately 5% circulates in a non-protein-bound or "free" state (2). However, the biological role of CBG may extend beyond that of a simple carrier molecule (3). For instance, as a serine proteinase inhibitor (serpin) family member, CBG undergoes a conformational change upon interaction with neutrophil elastase, which disrupts ste-95 (10) :E142-E150 jcem.endojournals.org E143 E144 Perogamvros et al. Novel G237V CBG Variant J Clin Endocrinol Metab, October 2010, 95(10):E142-E150 E146 Perogamvros et al. Novel G237V CBG Variant J Clin Endocrinol Metab, October 2010, 95(10):E142-E150 Downloaded from https://academic.oup.com/jcem/article-abstract/95/10/E142/2835299 by guest on 26 July 2018 E148 Perogamvros et al. Novel G237V CBG Variant J Clin Endocrinol Metab, October 2010, 95(10):E142-E150 J Clin Endocrinol Metab, October 2010, 95(10):E142-E150 jcem.endojournals.org E149 E150 Perogamvros et al. Novel G237V CBG Variant J Clin Endocrinol Metab, October 2010, 95(10):E142-E150