Glucocorticoid receptor mutations and clinical sensitivity to glucocorticoid in Chinese multiple sclerosis patients
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ORIGINAL ARTICLE
Glucocorticoid receptor mutations and clinical sensitivity to glucocorticoid in Chinese multiple sclerosis patients Tian Song 1,2 & Haoxiao Chang 1,2 & Li Du 1,2 & Linlin Yin 1,2 & Fudong Shi 1,2 & Xinghu Zhang 1,2 Received: 6 September 2019 / Accepted: 26 March 2020 # The Author(s) 2020
Abstract Background Glucocorticoid (GC) is the first-line therapy in acute attacks of multiple sclerosis (MS), but its efficacy is individually variable and may be associated with glucocorticoid receptor (GR) gene. Objective To establish the association between GR gene sequence and clinical GC sensitivity in Chinese MS patients. And to investigate the expression differences of serum GRα and FK506 binding protein 5 (FKBP5) in GC responders and non-responders. Materials and methods Coding exons 2–9 of the GR gene from 97 MS patients were sequenced. We performed ELISA to detect serum GRα and FKBP5 before the GC impulse therapy in patients with different GC sensitivities (according to the EDSS changes before and after the GC medication). Results Seven new mutations were located in exon 2, but the presence or absence of mutations was not associated with the response to GC therapy (P = 0.416). The GC-sensitive patients had higher GRα (P = 0.011) but lower FKBP5 (P = 0.025) levels in the serum. Conclusions The GR mutations detected in our study were not associated with the response to GC in Chinese MS patients. Higher GRα and lower FKBP5 levels in the serum might predict the response to GC, which may provide potential therapeutic target for GC-resistant patients with acute MS attack. Keywords Glucocorticoid receptor . Mutations . GRα . FKBP5 . Multiple sclerosis
Introduction Multiple sclerosis (MS) is an inflammatory disease of central nervous system (CNS) which generally begins in early adulthood. Glucocorticoids (GC) have anti-inflammatory and immunosuppressive properties and are thus recommended as the firstline therapy in the management of acute attacks of MS [1]. However, in the clinical practice, we found individual variability in GC efficacy. Some patients were resistant to GC initially, but in some other patients, the response to GC attenuated with Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10072-020-04376-8) contains supplementary material, which is available to authorized users. * Tian Song [email protected] 1
Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
2
China National Clinical Research Center for Neurological Diseases, Beijing 100070, China
relapses (secondly resistant) [2]. In recent years, several largescale databases reveal this point in real-world observational studies [3]. The mechanism governing the responsiveness of GC action remains elusive [4, 5]. Multiple factors can influence cellular glucocorticoid sensitivity at the level of the glucocorticoid receptor (GR) and its signaling pathway, including cochaperones such as FK506-binding protein 5 (FKBP5) [6, 7]. The GR gene can give rise t
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