Reduced DNA methylation of FKBP5 in Cushing’s syndrome
Open accessAbstract
FKBP5 encodes a co-chaperone of HSP90 protein that regulates intracellular glucocorticoid receptor sensitivity. When it is bound to the glucocorticoid receptor complex, cortisol binds with lower affinity to glucocorticoid receptor. Cushing's syndrome is associated with memory deficits, smaller hippocampal volumes, and wide range of cognitive impairments. We aimed at evaluating blood DNA methylation of FKBP5 and its relationship with memory and hippocampal volumes in Cushing's syndrome patients. Polymorphism rs1360780 in FKBP5 has also been assessed to determine whether genetic variations can also govern CpG methylation. Thirty-two Cushing's syndrome patients and 32 matched controls underwent memory tests, 3-Tesla MRI of the brain, and DNA extraction from total leukocytes. DNA samples were bisulfite treated, PCR amplified, and pyrosequenced to assess a total of 41CpG-dinucleotides in the introns 1, 2, 5, and 7 of FKBP5. Significantly lower intronic FKBP5 DNA methylation in CS patients compared to controls was observed in ten CpG-dinucleotides. DNA methylation at these CpGs correlated with left and right HV (Intron-2-Region-2-CpG-3: LHV, r = 0.73, p = 0.02; RHV, r = 0.58, p = 0.03). Cured and active CS patients showed both lower methylation of intron 2 (92.37, 91.8, and 93.34 %, respectively, p = 0.03 for both) and of intron 7 (77.08, 73.74, and 79.71 %, respectively, p = 0.02 and p < 0.01) than controls. Twenty-two subjects had the CC genotype, 34 had the TC genotype, and eight had the TT genotype. Lower average DNA methylation in intron 7 was observed in the TT subjects compared to CC (72.5vs. 79.5 %, p = 0.02) and to TC (72.5 vs. 79.0 %, p = 0.03). Our data demonstrate, for the first time, a reduction of intronic DNA methylation of FKBP5 in CS patients.
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Epigenomic alterations are associated with pathologies characterized by behavioral or/and cognitive problems, e.g., Alzheimer's disease, Rett syndrome, Cushing's syndrome, depression, addiction, aggression and antisocial behavior, and also with illnesses characterized by childhood trauma exposures, such as mental disorders.
“Epigenomic alterations are also associated with pathologies characterized by behavioral or/and cognitive problems, e.g., Alzheimer’s disease (69), Rett syndrome (70), Cushing’s syndrome (71), depression (72), addiction (73), aggression and antisocial behavior (74), and also with illnesses characterized by childhood trauma exposures, such as mental disorders (75).”
From Epigenetic Modifications in Stress Response Genes Associated With Childhood Trauma (2019) · cites this paper as [71]
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- Authors
- Resmini, E., Santos, A., Aulinas, A., Webb, S. M., Vives-Gilabert, Y., Cox, O., Wand, G., & Lee, R. S.
- Affiliations
- Universitat Autònoma de Barcelona (ES)
- Johns Hopkins University (US)
- Corresponding author
- Resmini, Eugenia
- Venue
- Endocrine
- Published
- 2016-09-23
- Volume
- 54
- Issue
- 3
- Pages
- 768-777
- ISSN
- 0969-711X (ISSN-L)
- 1355-008X
- 1559-0100
- PMC
- PMC6391874
- OpenAlex
- W2522400862
- Cited by
- 42
- References
- 30
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 5 · 2023: 2 · 2022: 4 · 2021: 5 · 2020: 8 · 2019: 4 · 2018: 5 · 2017: 6
- FWCI
- 5.03
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Endocrine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Spanish Ministry of Science and Innovation (FIS080302)
- European Commission (ERCUSYN PHP800200)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- Cushing's syndrome, FKBP5, DNA methylation, glucocorticoid receptor, Hsp90 co-chaperone, hippocampal volume, memory impairment, leukocyte DNA, epigenetics
- MeSH terms
- Tacrolimus Binding Protein 5, Adult, Cross-Sectional Studies, Cushing Syndrome, Female, Genotype, Humans, Male, Middle Aged, Case-Control Studies, CpG Islands, DNA Methylation, Tacrolimus Binding Proteins
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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