Corticosteroid-Binding Globulin Gene Mutations and Chronic Fatigue/Pain Syndromes: An Overview of Current Evidence (original) (raw)

2012, An International Perspective on the Future of Research in Chronic Fatigue Syndrome

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' (SR) 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 .