Clinical manifestations of highly prevalent corticosteroid-binding globulin mutations in a village in southern Italy (original) (raw)
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An International Perspective on the Future of Research in Chronic Fatigue Syndrome, 2012
Several lines of evidence suggest that corticosteroid-binding globulin (CBG), long known as a cortisol-transport glycoprotein, may have broader roles in targeted-tissue hormone delivery and the neurobehavioural responses to stress. These include studies of individual kindreds with rare severe CBG gene (SERPINA6) mutations, a study of chronic fatigue patients, a community study of individuals with a relatively high prevalence of two function altering CBG gene mutations in Calabria, Italy, a study of the genetic epidemiology of chronic pain, and, finally, two separate animal CBG gene knockout models. 2. Corticosteroid-binding globulin: Structure and function CBG circulates as a 383 amino acid (50-55kDa) glycoprotein in blood, and was discovered in the late 1950s 1-6 as a transport glycoprotein for cortisol in human plasma 7,8. The liver is the main source of circulating CBG, although gene expression is also present in the placenta and kidney, and CBG is differentially expressed according to developmental stage in foetal life 9,10. CBG is highly glycosylated with six consensus sites for N-glycosylation and sialyation 11. Each molecule contains a single high-affinity (Ka = 1.7x 10 8) cortisol binding site 12,13 , for which glycosylation at Asn 238 appears to be critical, probably due to the effect of this glycosylation site on tertiary structure 14. Deglycosylation of the mature protein does not alter cortisol binding affinity. CBG is a Clade A member of the serine protease inhibitor (serpin) superfamily, however it lacks intrinsic serine protease inhibitory activity 15,16. The CBG (SERPINA6) gene is located in a group of other serine protease inhibitor genes, thought to be phylogenetically related, on chromosome 14q31-q32.1 17. Approximately 80% of circulating cortisol under basal conditions is bound to CBG. About 5-8% of the cortisol is in a free or an unfractionated state, which is generally thought to be the biologically active form, and the remainder is loosely bound to high capacity albumin 18. CBG, as part of its biological function, undergoes a so called 'stressed to relaxed' (SR) conformational change following the cleavage of its surface-exposed loop called the reactive centre loop or RCL 18. However, the mode of cleavage in CBG differs from other members of www.intechopen.com An International Perspective on the Future of Research in Chronic Fatigue Syndrome 70 the serpin superfamily 19. The RCL of CBG is cleaved by human leukocyte elastase (HLE) at sites of inflammation 10,20 rather than by inhibiting proteinases 18. The HLE cleavage of CBG results in a tenfold decrease in its binding affinity 21 , thus releasing cortisol 10. In states of stress such as sepsis 22 , burns 23 and myocardial infarction 24 , the free cortisol percentage increases to up to 20%, due to the saturation of available CBG by increased cortisol and reduced CBG levels (a result of increased CBG cleavage/catabolism and inhibited synthesis) 25,26. Inflammatory cytokines such as IL-6, glucocorticoids, insulin, hyperthyroidism, nephrotic syndrome, and cirrhosis can also reduce CBG concentrations. On the other hand, oestrogen and pregnancy can increase CBG concentrations 10,27. It is interesting to note, in this context, that increased production of HLE by neutrophils has been reported in chronic fatigue syndrome 20,28. 3. Corticosteroid-binding globulin: More than just a transport glycoprotein CBG has traditionally been considered to be a transport vehicle for the water insoluble cortisol 29 , with perhaps some role in moderating release of free cortisol in times of cortisol excess or deficiency 30. This is in keeping with the 'free hormone hypothesis' proposed by Mendel 31 , which states that the biological activity of a hormone depends on the free rather than its protein-bound concentrations. The free steroid hormone can cross the plasma membrane of the target cell due to its small size and lipid solubility 32 .
Clinical Endocrinology, 2007
Corticosteroid-binding globulin (CBG) binds cortisol with high affinity, facilitating transport of cortisol in blood, although tissuespecific CBG-cortisol interactions have long been postulated. There are three heritable, human CBG gene mutations that can reduce CBG-cortisol binding affinity and/or reduce circulating CBG levels. In some families, fatigue and low blood pressure have been associated with affinity altering or CBG level reducing mutations. The limited numbers of reports raise the possibility of ascertainment bias as many cases presented with features suggesting cortisol deficiency. The recent description of a genetically CBG-deficient mouse listed fatigue, manifest as reduced activity levels, as part of the phenotype, which also included immune aberrations. Severe CBG mutations may produce fatigue, but one study suggests that these are a rare cause of idiopathic fatigue. A mechanism for the effect of CBG mutations on fatigue is not readily apparent because free cortisol levels are normal, although we speculate that CBG may have an effect on cortisol-brain transport.
Clinical Endocrinology, 2003
family was studied and correlations between genotype and serum cortisol, cortisol binding capacity (CBC) and CBG levels were determined. SUBJECTS All 10 family members, comprising three generations, and nine healthy volunteers were studied. MEASUREMENTS Genomic DNA was extracted from white blood cells from all family members. The human CBG exons 2-5 were amplified by PCR, submitted to automatic sequencing. Cortisol and CBG levels in serum were measured by radioimmunoassay (RIA). CBC in serum was determined using tritiated cortisol and other cortisol binding parameters were calculated through Scatchard analysis. RESULTS A missense mutation in exon 5 of CBG (1254G → → → → A; Asp367Asn), recently described as CBG Lyon, was found in all family members. The proband and one sister were homozygous whereas all other family members, including parents, were heterozygous for this mutation. Cortisol levels in the only two homozygotes were lower than in heterozygotes and both were significantly lower as compared to controls (69 and 182 nmol/l vs. 267 ± ± ± ± 129 nmol/l vs. 459 ± ± ± ± 195 nmol/l, respectively, P < 0·05). CBC was decreased in the two homozygotes as compared to heterozygotes and in both groups as compared to controls (< 90 and 114 nmol / l vs. 305·0 ± ± ± ± 81·4 nmol / l vs. 594·8 ± ± ± ± 59·5 nmol / l, respectively, P < 0·05). CBG levels were lower in homozygotes as compared to heterozygotes and in both as compared to controls (325 and 375 nmol / l vs. 496·75 ± ± ± ± 50·75 nmol / l vs. 647·25 ± ± ± ± 87·50 nmol / l, respectively, P < 0·05). CONCLUSIONS An abnormal CBG resulting from a missense mutation and known as CBG Lyon was found in this Brazilian kindred. This abnormal CBG has decreased affinity for cortisol and results in low or low normal serum cortisol levels in homozygous and heterozygous subjects. Although relative hypotension and fatigue have recently been associated with CBG deficiency in a family with two CBG mutations (null and Lyon), the two homozygous subjects in this kindred were both normotensive and only the proband presented with fatigue.
PLOS Genetics, 2014
Variation in plasma levels of cortisol, an essential hormone in the stress response, is associated in population-based studies with cardio-metabolic, inflammatory and neuro-cognitive traits and diseases. Heritability of plasma cortisol is estimated at 30-60% but no common genetic contribution has been identified. The CORtisol NETwork (CORNET) consortium undertook genome wide association meta-analysis for plasma cortisol in 12,597 Caucasian participants, replicated in 2,795 participants. The results indicate that ,1% of variance in plasma cortisol is accounted for by genetic variation in a single region of chromosome 14. This locus spans SERPINA6, encoding corticosteroid binding globulin (CBG, the major cortisol-binding protein in plasma), and SERPINA1, encoding a1-antitrypsin (which inhibits cleavage of the reactive centre loop that releases cortisol from CBG). Three partially independent signals were identified within the region, represented by common SNPs; detailed biochemical investigation in a nested sub-cohort showed all these SNPs were associated with variation in total cortisol binding activity in plasma, but some variants influenced total CBG concentrations while the top hit (rs12589136) influenced the immunoreactivity of the reactive centre loop of CBG. Exome chip and 1000 Genomes imputation analysis of this locus in the CROATIA-Korcula cohort identified missense mutations in SERPINA6 and SERPINA1 that did not account for the effects of common variants. These findings reveal a novel common genetic source of variation in binding of cortisol by CBG, and reinforce the key role of CBG in determining plasma cortisol levels. In turn this genetic variation may contribute to cortisol-associated degenerative diseases.
Journal of the Endocrine Society, 2021
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 glucos...
Pain Research and …, 2011
In complex multisymptom disorders like fibromyalgia syndrome (FMS) and chronic fatigue syndrome (CFS) that are defined primarily by subjective symptoms, genetic and gene expression profiles can provide very useful objective information. This paper summarizes research on genes that may be linked to increased susceptibility in developing and maintaining these disorders, and research on resting and stressor-evoked changes in leukocyte gene expression, highlighting physiological pathways linked to stress and distress. These include the adrenergic nervous system, the hypothalamic-pituitary-adrenal axis and serotonergic pathways, and exercise responsive metabolite-detecting ion channels. The findings to date provide some support for both inherited susceptibility and/or physiological dysregulation in all three systems, particularly for catechol-O-methyl transferase (COMT) genes, the glucocorticoid and the related mineralocorticoid receptors (NR3C1, NR3C2), and the purinergic 2X4 (P2X4) ion channel involved as a sensory receptor for muscle pain and fatigue and also in upregulation of spinal microglia in chronic pain models. Methodological concerns for future research, including potential influences of comorbid clinical depression and antidepressants and other medications, on gene expression are also addressed.
Glucocorticoid receptor variants: clinical implications
The Journal of Steroid Biochemistry and Molecular Biology, 2002
Following exposure to stress, cortisol is secreted from the adrenal cortex under the control of the hypothalamic-pituitary-adrenal axis (HPA-axis). Central in the regulation of the HPA-axis is a two tied corticosteroid-receptor system, comprised of high and low affinity receptors, the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR), respectively. In addition, these corticosteroid receptors mediate the effects of cortisol during stress on both central and peripheral targets. Cortisol modulates gene-expression of corticosteroid-responsive genes, with the effect lasting from hours to days.
PloS one, 2015
Chronic widespread muscoloskeletal pain (CWP) is prevalent in the general population and associated with high health care costs, so understanding the risk factors for chronic pain is important for both those affected and for society. In the present study we investigated the underlying etiological structure of CWP to understand better the association between the major clinical features of fatigue, depression and dihydroepiandrosterone sulphate (DHEAS) using a multivariate twin design. Data were available in 463 UK female twin pairs including CWP status and information on depression, chronic fatigue and serum DHEAS levels. High to moderate heritabilities for all phenotypes were obtained (42.58% to 74.24%). The highest phenotypic correlation was observed between fatigue and CWP (r = 0.45), and the highest genetic correlation between CWP and fatigue (rg = 0.78). Structural equation modeling revealed the AE Cholesky model to provide the best model of the observed data. In this model, two...