Naturally Occurring Mutations of Human Corticosteroid-Binding Globulin

Simard, Marc; Hill, Lesley A.; Lewis, John G.; Hammond, Geoffrey L.

doi:10.1210/jc.2014-3130

Cited by 33 publications

(48 citation statements)

References 39 publications

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“…The steroid-binding activity of CBG is undetectable in rat plasma samples in which CBG appears to be have undergone proteolysis, and this is in line with a marked loss in cortisol-binding affinity observed when the RCL of human CBG is cleaved by neutrophil elastase (Hammond , et al 1990), chymotrypsin (Simard , et al 2015) or the bacterial proteinase, LasB (Simard , et al 2014). However, our observations of in vivo rat CBG proteolysis under pathophysiological conditions contrasts with a previous report that E-coli produced rat CBG, mutated to allow for cleavage by human neutrophil elastase, only undergoes a 2-fold reduction in binding affinity (Gardill , et al 2012).…”

Section: Discussionmentioning

confidence: 54%

“…Genome-wide sequencing of human populations has also identified numerous other single nucleotide polymorphisms that cause decreased CBG production or defects in steroid binding, some of which are enriched in specific ethnic groups (Simard , et al 2015). Although patients with CBG deficiencies have been reported to suffer from a variety of symptoms including chronic pain, fatigue, depression, hypotension and excess body weight (Gagliardi , et al 2010), it remains to be determined how well they cope with severe, acute inflammation.…”

Section: Introductionmentioning

confidence: 99%

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Corticosteroid-binding globulin is a biomarker of inflammation onset and severity in female rats

Hill

Bodnar

Weinberg

et al. 2016

Journal of Endocrinology

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Plasma corticosteroid-binding globulin (CBG) plays a critical role in regulating glucocorticoid bioavailability and is an acute phase “negative” protein during inflammation. In an adjuvant-induced arthritis model, plasma CBG levels decrease in rats that develop severe inflammation, and we have now determined when and how these reductions in CBG occur. After administering complete Freund's adjuvant or saline intra-dermally at the tail base, blood samples were taken periodically for 16 days. In adjuvant-treated rats, decreases in plasma CBG levels matched the severity of inflammation, and decreases were observed 4 days before any clinical signs of inflammation. Decreases in CBG levels coincided with an ∼5kDa reduction in its apparent size, consistent with proteolytic cleavage, and cleaved CBG lacked steroid-binding activity. At the termination of the experimental period, hepatic Cbg mRNA levels were decreased in rats with severe inflammation. While plasma TNF-α increased in all adjuvant-treated rats, increases in Il-4, IL-6, IL-10, IL-13, and IFN-γ were only observed in rats with cleaved CBG. Rats with cleaved CBG also exhibited increased spleen weights, and strong negative correlations were observed between CBG, IL-6 and spleen weights, respectively. However, there were no differences in hepatic Cbg mRNA levels in relation to the apparent proteolysis of CBG, suggesting that CBG cleavage occurs prior to changes in hepatic Cbg expression. Our results indicate that the levels and integrity of plasma CBG are biomarkers of the onset and severity of inflammation. Dynamic changes in the levels and function of CBG likely modulate the tissue availability of corticosterone during inflammation.

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Section: Discussionmentioning

confidence: 54%

Section: Introductionmentioning

confidence: 99%

Corticosteroid-binding globulin is a biomarker of inflammation onset and severity in female rats

Hill

Bodnar

Weinberg

et al. 2016

Journal of Endocrinology

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“…With only six matched tumor and normal DNA pairs, Pasqualucci et al 13 already identified by whole-exome sequencing 106 rare germline variants among which the SERPINA6 gene. This gene is involved in corticosteroid bioavailability by encoding corticosteroid-binding globulin 92 and it is also targeted by somatic mutations in DLBCL (Supplementary Table s1). Many of the germline variants described by Pasqualucci et al belong to the same functional classes of genes that are somatically mutated in this disease and could well be relevant for its development.…”

Section: Genes With Less Obvious Causalitymentioning

confidence: 99%

Germline mutations predisposing to diffuse large B-cell lymphoma

Leeksma

Miranda

Veelken

2017

Blood Cancer Journal

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Genetic studies of diffuse large B-cell lymphomas (DLBCLs) in humans have revealed numerous targets of somatic mutations and an increasing number of potentially relevant germline alterations. The latter often affect genes involved in DNA repair and/or immune function. In general, defects in these genes also predispose to other conditions. Knowledge of these mutations can lead to disease-preventing measures in the patient and relatives thereof. Conceivably, these germline mutations will be taken into account in future therapy of the lymphoma. In other hematological malignancies, mutations originally found as somatic aberrations have also been shown to confer predisposition to these diseases, when occurring in the germline. Further interrogations of the genome in DLBCL patients are therefore expected to reveal additional hereditary predisposition genes. Our review shows that germline mutations have already been described in over one-third of the genes that are somatically mutated in DLBCL. Whether such germline mutations predispose carriers to DLBCL is an open question. Symptoms of the inherited syndromes associated with these genes range from anatomical malformations to intellectual disability, immunodeficiencies and malignancies other than DLBCL. Inherited or de novo alterations in protein-coding and non-coding genes are envisioned to underlie this lymphoma.

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“…Hypoalbuminemia and alterations in the binding of cortisol may lead to subnormal total cortisol responses to ACTH, while the free cortisol response can remain entirely normal in subjects with severe acute illness [9]. Other examples in which free cortisol measurement becomes particularly important are the rare cases of inactive corticosteroid-binding globulin, such as CBG-Lyon [10] or congenital CBG deficiency [11,12]. The current consensus is that the free rather than the protein-bound fraction of cortisol is responsible for its physiological function [4].…”

Section: Introductionmentioning

confidence: 99%

Establishing Normal Ranges of Basal and ACTH-Stimulated Serum Free Cortisol in Children

Eyal¹,

Limor

Oren³

et al. 2016

Horm Res Paediatr

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Background: Normative data have been established for stimulated serum total cortisol in children but not for serum free cortisol. Methods: Children who were referred for ACTH testing to rule out adrenal insufficiency were enrolled. Only children with normal response and normal androgen levels were included. Total cortisol was determined by a chemiluminescence method, and free cortisol was measured by the same method following equilibrium dialysis. Results: The study group consisted of 85 subjects (28 male; 57 female) with a median age of 8.5 years (range 0.6-17.7). The mean basal and peak total cortisol levels were 11.5 ± 5.7 and 32.9 ± 6.2 μg/dl, respectively. The mean basal and peak free cortisol levels were 0.4 ± 0.3 and 1.8 ± 0.6 μg/dl, respectively. There was a negative correlation between peak total cortisol and age but not between peak free cortisol and age. The 3rd and 97th percentile values for peak free cortisol were 0.94 μg/dl (26 nmol/l) and 2.97 μg/dl (82 nmol/l), respectively. Conclusions: Measurement of free cortisol has the advantage of being independent of cortisol-binding globulin levels. This study provides reference ranges for stimulated free cortisol in children, with a cutoff value of 0.9 μg/dl (25 nmol/l) as a normal response to a standard ACTH test.

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Naturally Occurring Mutations of Human Corticosteroid-Binding Globulin

Abstract: Our data provide insight into how specific residues affect CBG secretion or function and illustrate the need to consider the various naturally occurring human CBG mutations in clinical evaluations of diseases associated with abnormalities in cortisol levels or activity.

Cited by 33 publications

References 39 publications

Corticosteroid-binding globulin is a biomarker of inflammation onset and severity in female rats

Corticosteroid-binding globulin is a biomarker of inflammation onset and severity in female rats

Germline mutations predisposing to diffuse large B-cell lymphoma

Establishing Normal Ranges of Basal and ACTH-Stimulated Serum Free Cortisol in Children

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