The phase-shift mutation in the glucocorticoid receptor gene: potential etiologic significance of neuroendocrine mechanisms in lupus nephritis

Abstract

Background: Glucocorticoid (GC), a mediator of the hypothalamo–pituitary–adrenal axis, has been found to play an important role in maintaining the stability of immune endo-environment of the body. The pathogenesis of lupus nephritis, an autoimmune disease, is thought to be related to the intrinsic hyposensitivity to GC secreted by adrenal gland, and impairs the regulation of the immuno–neuro–endocrine axis. Methods: To test this hypothesis, we examined the response of 39 clinic patients with lupus nephritis to GC and analyzed the molecular structure and function of the GC receptor (GR) on peripheral blood mononuclear cells. Results: There was no difference in the level of ACTH, GC and ligand affinity of GR between the patients and the controls. The GR number on mononuclear cells of lupus patients was lower than that of the controls. There was no difference in GR number between the patients with heterogeneous response, i.e. sensitive, dependent and resistance, to GC. The analysis of exon 9 of the GC receptor with PCR-amplified single strand conformation polymorphism (PCR-SSCP) method showed the polymorphism in exon 9 of GC receptor in 8 of the 39 lupus nephritis patients. DNA sequence analysis revealed an adenine insertion at the 2439 base pair of the GC receptor gene. This phase-shift mutation caused an additional 20 amino acids being translated into protein of GC receptor. Conclusion: The decreased number of GC receptor and the molecular variation of GR on mononuclear cells could explain the phenomenon of GC resistance, potentially to endogenous GC, which suggested an etiological significance of neuro–endocrine–immune mechanism in lupus nephritis. This may be useful in the design of lupus nephritis therapy.