Dataset Information

CBG Montevideo: A Clinically Novel SERPINA6 Mutation Leading to Haploinsufficiency of Corticosteroid-binding Globulin.

ABSTRACT: Corticosteroid-binding globulin (CBG) is the main transport protein for cortisol, binding up to 90% in a 1:1 ratio. CBG provides transport of cortisol within the circulation and targeted cortisol tissue delivery. Here, we describe the clinically novel "CBG Montevideo" a SERPINA6 pathogenic variant that results in a 50% reduction in plasma CBG levels. This was associated with low serum total cortisol and clinical features of hypoglycemia, exercise intolerance, chronic fatigue, and hypotension in the proband, a 7-year-old boy, and his affected mother. Previous reports of 9 human CBG genetic variants affecting either CBG concentrations or reduced CBG-cortisol binding properties have outlined symptoms consistent with attenuated features of hypocortisolism, fatigue, and hypotension. Here, however, the presence of hypoglycemia, despite normal circulating free cortisol, suggests a specific role for CBG in effecting glucocorticoid function, perhaps involving cortisol-mediated hepatic glucose homeostasis and cortisol-brain communication.

SUBMITTER: Meyer EJ

PROVIDER: S-EPMC8294686 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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CBG Montevideo: A Clinically Novel <i>SERPINA6</i> Mutation Leading to Haploinsufficiency of Corticosteroid-binding Globulin.

Meyer Emily Jane EJ Spangenberg Lucía L Ramírez Maria José MJ De Sousa Sunita Maria Christina SMC Raggio Victor V Torpy David James DJ

Journal of the Endocrine Society 20210622 9

Corticosteroid-binding globulin (CBG) is the main transport protein for cortisol, binding up to 90% in a 1:1 ratio. CBG provides transport of cortisol within the circulation and targeted cortisol tissue delivery. Here, we describe the clinically novel "CBG Montevideo" a <i>SERPINA6</i> pathogenic variant that results in a 50% reduction in plasma CBG levels. This was associated with low serum total cortisol and clinical features of hypoglycemia, exercise intolerance, chronic fatigue, and hypotens ...[more]

PMID: 34308089

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Project description:BackgroundPatients with adrenal insufficiency are treated with oral hydrocortisone (HC) to compensate for the loss of endogenous cortisol production. Intrinsic imperfections of cortisol replacement strategies in mimicking normal cortisol secretion are the underlying cause of the increased morbidity and mortality of patients suffering from secondary adrenal insufficiency (SAI). To improve oral hydrocortisone substitution therapy, a better understanding of its pharmacokinetics (PK) is necessary. The previous PK model did not include protein binding. It is known that protein binding can impact hydrocortisone pharmacokinetics. The aim of this study is to describe HC pharmacokinetics including the protein-binding state using Edsim++ (Mediware, Prague) pharmacokinetic modeling software, paving the way for an in-silico tool suitable for drug delivery design.MethodsA total of 46 patients with SAI participated in a randomized double-blind crossover study Patients randomly received a low dose of HC (0.2-0.3 mg/kg body weight/day) for 10 weeks, followed by a high dose (0.4-0.6 mg/kg body weight/day) for another 10 weeks, or vice versa. Plasma samples were obtained and analyzed for free and total hydrocortisone. Single compartment population pharmacokinetic analysis was performed using an extended Werumeus-Buning model built in Edsim++. This model includes a mathematical approach for estimating free cortisol by Nguyen et al., taking the protein binding of HC to albumin and hydrocortisone-binding globulin (CBG, transcortin) into consideration, as well as different states of CBG which affect binding kinetics to HC. The goodness of fit for observed versus predicted values was calculated.Results and conclusionsNguyen's formula for free cortisol estimation was successfully implemented in a pharmacokinetic model. The model shows high Spearman's correlation for observed versus predicted hydrocortisone concentrations. Significantly higher correlations (Spearman's r, 0.901 vs. 0.836) between total and free hydrocortisone AUC24 (area-under the curve over 24 h) are found when comparing new and old models. This new model was used to simulate the plasma concentration-time behavior of a more suitable hydrocortisone formulation.

Dataset Information

CBG Montevideo: A Clinically Novel SERPINA6 Mutation Leading to Haploinsufficiency of Corticosteroid-binding Globulin.

Publications

CBG Montevideo: A Clinically Novel <i>SERPINA6</i> Mutation Leading to Haploinsufficiency of Corticosteroid-binding Globulin.

Similar Datasets

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