Primary Generalized Glucocorticoid Resistance and Hypersensitivity

Professor Evangelia Charmandari

MD, MSc, PhD, MRCP(UK), CCST(UK)
Professor of Pediatrics – Pediatric and Adolescent Endocrinology
National and Kapodistrian University of Athens Medical School
First Department of Pediatrics, ‘Aghia Sophia’ Children’s Hospital

Primary Generalized Glucocorticoid Resistance (PGGR) is a rare, familial or sporadic condition characterized by generalized, partial, target-tissue insensitivity to glucocorticoids, which leads to compensatory activation of the HPA axis and hypersecretion of ACTH in the systemic circulation. On the other hand, Primary Generalized Glucocorticoid Hypersensitivity (PGGH) represents the mirror image of PGGR, and is characterized by generalized, partial, target-tissue hypersensitivity to glucocorticoids, and compensatory hypoactivation of the HPA axis. The molecular basis of these conditions has been attributed to mutations in the glucocorticoid receptor (hGR) gene, which impair glucocorticoid signal transduction and alter tissue sensitivity to glucocorticoids. To date, 17 mutations of the hGR gene have been associated with PGGR and 1 with PGGH.

During her years at the NIH and later at the BRFAA, Professor Evangelia Charmandari studied the molecular mechanisms of glucocorticoid action and in particular the molecular mechanisms underlying the syndromes of Primary Generalized Glucocorticoid Resistance and Hypersensitivity. She identified five novel mutations of the hGR gene in patients with those conditions and determined the molecular mechanisms through which various natural hGR mutants impair glucocorticoid signal transduction.

Publications

23. Hurt DE, Suzuki S, Mayama T, Charmandari E, Kino T. Structural analysis of the pathologic mutant glucocorticoid receptor ligand-binding domains. Molecular Endocrinology 2016; 2016; 30(2): 173-88.

22. Nicolaides NC, Lamprokostopoulou A, Sertedaki A, Charmandari E. Recent advances in the molecular mechanisms causing primary generalized glucocorticoid resistance. Hormones (Athens) 2016; 15(1): 23-34.

21. Nicolaides NC, Skyrla E, Vlachakis D, Psarra AM, Moutsatsou P, Sertedaki A, Kossida S, Charmandari E. Functional characterization of the hGRαT556I causing Chrousos syndrome. European Journal of Clinical Investigation 2016; 46(1): 42-9.

20. Nicolaides NC, Lamprokostopoulou A, Polyzos A, Kino T, Katsantoni E, Triantafyllou P, Christophoridis A, Katzos G, Dracopoulou M, Sertedaki A, Chrousos GP, Charmandari E. Transient Generalized Glucocorticoid Hypersensitivity. European Journal of Clinical Investigation 2015; 45(12): 1306-15.

19. Nicolaides NC, Geer EB, Vlachakis D, Roberts ML, Psarra AM, Moutsatsou P, Sertedaki A, Kossida S, Charmandari E. A novel mutation of the hGR gene causing Chrousos syndrome. European Journal of Clinical Investigation 2015; 45(8): 782-91.

18. Nicolaides NC, Roberts ML, Kino T, Braatvedt G, Hurt DE, Katsantoni E, Sertedaki A, Chrousos GP, Charmandari E. A novel point mutation of the human glucocorticoid receptor gene causes primary generalized glucocorticoid resistance through impaired interaction with the LXXLL motif of the p160 coactivators: dissociation of the transactivating and transreppressive activities. Journal of Clinical Endocrinology & Metabolism 2014; 99(5): E902-7.

17. Roberts ML, Kino T, Nicolaides NC, Hurt DE, Katsantoni E, Sertedaki A, Komianou F, Kassiou K, Chrousos GP, Charmandari E. A novel point mutation in the DNA-binding domain (DBD) of the human glucocorticoid receptor causes primary generalized glucocorticoid resistance by disrupting the hydrophobic structure of its DBD. Journal of Clinical Endocrinology & Metabolism 2013; 98(4): E790-5.

16. Charmandari E Kino T, Chrousos G. Primary generalized glucocorticoid resistance (Chrousos syndrome) and hypersensitivity. Endocrine Development 2013; 24: 67-85.

15. Charmandari E. Primary generalized glucocorticoid resistance and hypersensitivity: the end-organ involvement in the stress response. Science Signaling 2012; 5(244): pt5.

14. Charmandari E. Primary generalized glucocorticoid resistance and hypersensitivity. Hormone Research 2011; 76(3): 145-55.

13. Charmandari E, Kino T. Chrousos syndrome: A seminal report, a phylogenetic enigma and the clinical implications of glucocorticoid signaling changes. European Journal of Clinical Investigation 2010; 40(10): 932-42.

12. Charmandari E, Chrousos GP, Kino T. Identification of natural human glucocorticoid receptor (hGR) mutations or polymorphisms and their functional consequences at the hormone-receptor interaction level. Methods in Molecular Biology 2009; 590:33-60.

11. Kino T, Ichijo T, Zachman K, Chrousos GP, Charmandari E. A novel point mutation in the amino terminal domain of the human glucocorticoid receptor (hGR) gene enhancing hGR-mediated gene expression. Journal of Clinical Endocrinology & Metabolism 2008; 93(12): 4963-8.

10. Charmandari E, Kino T, Ichijo T, Chrousos GP. Generalized glucocorticoid resistance: Clinical aspects, molecular mechanisms and implications of a rare genetic disorder. Journal of Clinical Endocrinology & Metabolism 2008; 93(5): 1563-72.

9. Charmandari E, Kino T, Ichijo T, Jubiz W, Mejia L, Zachman K, Chrousos GP. A novel point mutation in helix11 of the ligand-binding domain of the human glucocorticoid receptor gene causing generalized glucocorticoid resistance. Journal of Clinical Endocrinology & Metabolism 2007; 92(10): 3986 – 90.

8. Charmandari E, Kino T. Novel causes of generalized glucocorticoid resistance. Hormone and Metabolic Research 2007; 39(6): 445-450.

7. Charmandari E, Kino T, Ichijo T, Zachman K, Alatsatianos A, Chrousos GP. Functional characterization of the natural human glucocorticoid receptor (hGR) mutants hGRαR477H and hGRαG679S associated with generalized glucocorticoid resistance. Journal of Clinical Endocrinology & Metabolism 2006; 91(4): 1535-1543.

6. Kino T, Liu SH, Charmandari E, Chrousos GP. Clucocorticoid receptor mutants demonstrate increased motility inside the nucleus of living cells: Time of fluorescence recovery after photobleaching (FRAP) is an integrated measure of receptor function. Molecular Medicine 2004; 10(7-12): 80-88.

5. Charmandari E, Raji A, Kino T, Ichijo T, Tiulpakov A, Zachman K, Chrousos GP. A novel point mutation in the ligand-binding domain (LBD) of the human glucocorticoid receptor (hGR) causing generalized glucocorticoid resistance: The importance of C-terminus of hGR LBD in conferring transactivational activity. Journal of Clinical Endocrinology & Metabolism 2005; 90(6): 3696-3705.

4. Charmandari E, Kino T, Chrousos GP. Familial/Sporadic glucocorticoid resistance: clinical phenotype and molecular mechanisms. Annals of the New York Academy of Sciences 2004; 1024: 168-181.

3. Charmandari E, Kino T, Vottero A, Souvatzoglou E, Bhattacharyya N, Chrousos GP. Natural glucocorticoid receptor mutants causing generalized glucocorticoid resistance: molecular genotype, genetic transmission and clinical phenotype. Journal of Clinical Endocrinology & Metabolism 2004; 89(4): 1939-1949.

2. Kino T, DeMartino M, Charmandari E, Mirani M, Chrousos GP. Tissue glucocorticoid resistance/hypersensitivity syndromes. Journal of Steroid Biochemistry and Molecular Biology 2003; 85(2-5): 457-467.

1. Kino T, Vottero A, Charmandari E, Chrousos GP. Familial/sporadic glucocorticoid resistance syndrome and hypertension. Annals of the New York Academy of Sciences 2002; 970: 101-111.