ARMC5 variants in PRKAR1A-mutated patients modify cortisol levels and Cushing's syndrome.
Ontology highlight
ABSTRACT:
SUBMITTER: Maria AG
PROVIDER: S-EPMC9262153 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:BackgroundCorticotropin-independent macronodular adrenal hyperplasia may be an incidental finding or it may be identified during evaluation for Cushing's syndrome. Reports of familial cases and the involvement of both adrenal glands suggest a genetic origin of this condition.MethodsWe genotyped blood and tumor DNA obtained from 33 patients with corticotropin-independent macronodular adrenal hyperplasia (12 men and 21 women who were 30 to 73 years of age), using single-nucleotide polymorphism arrays, microsatellite markers, and whole-genome and Sanger sequencing. The effects of armadillo repeat containing 5 (ARMC5) inactivation and overexpression were tested in cell-culture models.ResultsThe most frequent somatic chromosome alteration was loss of heterozygosity at 16p (in 8 of 33 patients for whom data were available [24%]). The most frequent mutation identified by means of whole-genome sequencing was in ARMC5, located at 16p11.2. ARMC5 mutations were detected in tumors obtained from 18 of 33 patients (55%). In all cases, both alleles of ARMC5 carried mutations: one germline and the other somatic. In 4 patients with a germline ARMC5 mutation, different nodules from the affected adrenals harbored different secondary ARMC5 alterations. Transcriptome-based classification of corticotropin-independent macronodular adrenal hyperplasia indicated that ARMC5 mutations influenced gene expression, since all cases with mutations clustered together. ARMC5 inactivation decreased steroidogenesis in vitro, and its overexpression altered cell survival.ConclusionsSome cases of corticotropin-independent macronodular adrenal hyperplasia appear to be genetic, most often with inactivating mutations of ARMC5, a putative tumor-suppressor gene. Genetic testing for this condition, which often has a long and insidious prediagnostic course, might result in earlier identification and better management. (Funded by Agence Nationale de la Recherche and others.).
| S-EPMC4727443 | biostudies-literature
Project description:Objective: Germline ARMC5 mutations are considered to be the main genetic cause of primary macronodular adrenal hyperplasia (PMAH). PMAH is associated with high variability of cortisol secretion caused from subclinical hypercortisolism to overt Cushing's syndrome (CS), in general due to bilateral adrenal nodules and rarely could also be due to non-synchronic unilateral adrenal nodules. The frequency of adrenal incidentalomas (AI) associated with PMAH is unknown. This study evaluated germline allelic variants of ARMC5 in patients with bilateral and unilateral AI and in patients with overt CS associated with bilateral adrenal nodules. Methods: We performed a retrospective multicenter study involving 123 patients with AI (64 bilateral; 59 unilateral). We also analyzed 20 patients with ACTH pituitary independent overt CS associated with bilateral adrenal nodules. All patients underwent germline genotyping analysis of ARMC5; abdominal CT and were classified as normal, possible or autonomous cortisol secretion, according to the low doses of dexamethasone suppression test. Results: We identified only one pathogenic allelic variant among the patients with bilateral AI. We did not identify any pathogenic allelic variants of ARMC5 in patients with unilateral AI. Thirteen out of 20 patients (65%) with overt CS and bilateral adrenal nodules were carriers of pathogenic germline ARMC5 allelic variants, all previously described. The germline ARMC5 mutation was observed in only one patient with bilateral AI; it was associated with autonomous cortisol secretion and showed to be a familial form. Conclusion: The rarity of germline ARMC5 mutations in AI points to other molecular mechanisms involved in this common adrenal disorder and should be investigated. In contrast, patients with overt Cushing's syndrome and bilateral adrenal nodules had the presence of ARMC5 mutations that were with high prevalence and similar to the literature. Therefore, we recommend the genetic analysis of ARMC5 for patients with established Cushing's syndrome and bilateral adrenal nodules rather than patients with unilateral AI.
| S-EPMC7019100 | biostudies-literature
Project description:Carney complex (CNC) is an inherited neoplasia syndrome with endocrine overactivity. Its most frequent endocrine manifestation is primary pigmented nodular adrenocortical disease (PPNAD), a bilateral adrenocortical hyperplasia causing pituitary-independent Cushing's syndrome. Inactivating mutations in PRKAR1A, a gene encoding the type 1 alpha-regulatory subunit (R1alpha) of the cAMP-dependent protein kinase (PKA) have been found in 80% of CNC patients with Cushing's syndrome. To demonstrate the implication of R1alpha loss in the initiation and development of PPNAD, we generated mice lacking Prkar1a specifically in the adrenal cortex (AdKO). AdKO mice develop pituitary-independent Cushing's syndrome with increased PKA activity. This leads to autonomous steroidogenic genes expression and deregulated adreno-cortical cells differentiation, increased proliferation and resistance to apoptosis. Unexpectedly, R1alpha loss results in improper maintenance and centrifugal expansion of cortisol-producing fetal adrenocortical cells with concomitant regression of adult cortex. Our data provide the first in vivo evidence that loss of R1alpha is sufficient to induce autonomous adrenal hyper-activity and bilateral hyperplasia, both observed in human PPNAD. Furthermore, this model demonstrates that deregulated PKA activity favors the emergence of a new cell population potentially arising from the fetal adrenal, giving new insight into the mechanisms leading to PPNAD.
| S-EPMC2883593 | biostudies-literature
Project description:BackgroundPrader-Willi syndrome (PWS) is a multisymptomatic, rare, genetic, neurodevelopmental disorder in adults mainly characterized by hyperphagia, cognitive dysfunction, behavioral problems and risk of morbid obesity. Although endocrine insufficiencies are common, hypocortisolism is rare and knowledge on long-term cortisol concentrations is lacking. The aim of this study was to evaluate long-term cortisol levels in PWS by measurements of hair cortisol.MethodsTwenty-nine adults with PWS, 15 men and 14 women, median age 29 years, median BMI 27 kg/m2, were included. Scalp hair samples were analyzed for cortisol content using liquid-chromatography tandem-mass spectrometry. In addition, a questionnaire on auxology, medication and stress were included. For comparison, 105 age- and sex-matched participants from the population-based Lifelines Cohort study were included as controls. The mean hair cortisol between the groups were compared and associations between BMI and stress were assessed by a generalized linear regression model.ResultsIn the PWS group large variations in hair cortisol was seen. Mean hair cortisol was 12.8 ± 25.4 pg/mg compared to 3.8 ± 7.3 pg/mg in controls (p = 0.001). The linear regression model similarly showed higher cortisol levels in patients with PWS, which remained consistent after adjusting for BMI and stress (p = 0.023). Furthermore, hair cortisol increased with BMI (p = 0.012) and reported stress (p = 0.014).ConclusionLong-term cortisol concentrations were higher in patients with PWS compared to controls and increased with BMI and stress, suggesting an adequate cortisol response to chronic stress. Hair cortisol demonstrate promising applications in the context of PWS treatment and disease management.
| S-EPMC7654170 | biostudies-literature
Project description:Primary aldosteronism is one of the leading causes of secondary hypertension, causing significant morbidity and mortality. A number of genetic defects have recently been identified in primary aldosteronism, whereas we identified mutations in ARMC5, a tumor-suppressor gene, in cortisol-producing primary macronodular adrenal hyperplasia.We investigated a cohort of 56 patients who were referred to the National Institutes of Health for evaluation of primary aldosteronism for ARMC5 defects.Patients underwent step-wise diagnosis, with measurement of serum aldosterone and plasma renin activity followed by imaging, saline suppression and/or oral salt loading tests, plus adrenal venous sampling. Cortisol secretion was also evaluated; unilateral or bilateral adrenalectomy was performed, if indicated. DNA, protein, and transfection studies in H295R cells were conducted by standard methods.We identified 12 germline ARMC5 genetic alterations in 20 unrelated and two related individuals in our cohort (39.3%). ARMC5 sequence changes in 6 patients (10.7%) were predicted to be damaging by in silico analysis. All affected patients carrying a variant predicted to be damaging were African Americans (P = .0023).Germline ARMC5 variants may be associated with primary aldosteronism. Additional cohorts of patients with primary aldosteronism and metabolic syndrome, particularly African Americans, should be screened for ARMC5 sequence variants because these may underlie part of the known increased predisposition of African Americans to low renin hypertension.
| S-EPMC4454793 | biostudies-literature
Project description:The urinary free cortisol (UFC) test is widely used for the screening of Cushing's syndrome. This case study illustrates the potential failure of the UFC test to correctly diagnose Cushing's disease (CD), indicating that the use of other complementary tests may be necessary to diagnose this disease in some cases.
| S-EPMC5134332 | biostudies-literature
Project description:Cushing's syndrome (CS) is a disease which results from excessive levels of cortisol in the human body. The disorder is associated with various signs and symptoms which are also common for the general population not suffering from compound hypersecretion. Thus, more sensitive and selective methods are required for the diagnosis of CS. This follow-up study was conducted to determine which steroid metabolites could serve as potential indicators of CS and possible subclinical hypercortisolism in patients diagnosed with so called non-functioning adrenal incidentalomas (AIs). Urine samples from negative controls (n = 37), patients with CS characterized by hypercortisolism and excluding iatrogenic CS (n = 16), and patients with non-functioning AIs with possible subclinical Cushing's syndrome (n = 25) were analyzed using gas chromatography-mass spectrometry (GC/MS) and gas chromatograph equipped with flame ionization detector (GC/FID). Statistical and multivariate methods were applied to investigate the profile differences between examined individuals. The analyses revealed hormonal differences between patients with CS and the rest of examined individuals. The concentrations of selected metabolites of cortisol, androgens, and pregnenetriol were elevated whereas the levels of tetrahydrocortisone were decreased for CS when opposed to the rest of the study population. Moreover, after analysis of potential confounding factors, it was also possible to distinguish six steroid hormones which discriminated CS patients from other study subjects. The obtained discriminant functions enabled classification of CS patients and AI group characterized by mild hypersecretion of cortisol metabolites. It can be concluded that steroid hormones selected by applying urinary profiling may serve the role of potential biomarkers of CS and can aid in its early diagnosis.
| S-EPMC5343830 | biostudies-literature
Project description:BackgroundCushing's syndrome (CS) is a rare condition of chronically elevated cortisol levels resulting in diverse comorbidities, many of which endure beyond successful treatment affecting the quality of life. Few data are available concerning patients' experiences of diagnosis, care and persistent comorbidities.ObjectiveTo assess CS patients' perspectives on the diagnostic and care journey to identify unmet therapeutic needs.MethodsA 12-item questionnaire was circulated in 2019 by the World Association for Pituitary Organisations. A parallel, 13-item questionnaire assessing physician perceptions on CS patient experiences was performed.ResultsThree hundred twenty CS patients from 30 countries completed the questionnaire; 54% were aged 35-54 and 88% were female; 41% were in disease remission. The most burdensome symptom was obesity/weight gain (75%). For 49% of patients, time to diagnosis was over 2 years. Following treatment, 88.4% of patients reported ongoing symptoms including, fatigue (66.3%), muscle weakness (48.8%) and obesity/weight gain (41.9%). Comparisons with delay in diagnosis were significant for weight gain (P = 0.008) and decreased libido (P = 0.03). Forty physicians completed the parallel questionnaire which showed that generally, physicians poorly estimated the prevalence of comorbidities, particularly initial and persistent cognitive impairment. Only a minority of persistent comorbidities (occurrence in 1.3-66.3%; specialist treatment in 1.3-29.4%) were managed by specialists other than endocrinologists. 63% of patients were satisfied with treatment.ConclusionThis study confirms the delay in diagnosing CS. The high prevalence of persistent comorbidities following remission and differences in perceptions of health between patients and physicians highlight a probable deficiency in effective multidisciplinary management for CS comorbidities.
| S-EPMC9254293 | biostudies-literature
Project description:Patients with Cushing's syndrome (CS) frequently report impairments in cognitive and emotional functioning. Given neuroimaging research that implicates alterations in structure and function in the brain in this population, goals of this study were to investigate neuropsychological and emotional functioning, with particular emphasis on complex attention and memory. In a clinical sample of 18 adults with CS referred for neuropsychological evaluation (age 41.6 ± 10.6, 72% Caucasian), patients' most common subjective complaints were in attention and increased irritability. On objective testing, patients exhibited significant declines in the consistency of their sustained attention and visual-spatial functioning compared to normative peers. Patients exhibited on average significantly reduced initial learning following first exposure to visual and verbal stimuli but intact retention of information learned. Patients with CS endorsed highly elevated levels of somatization, depression, and anxiety, and 59% of them scored in the clinically elevated range for somatization and depressive symptomatology. Exploratory analyses suggested that the 11 patients with active Cushing's exhibited lower processing speed, poorer sustained attention, naming, and cognitive flexibility compared to the 7 patients who achieved biochemical remission. Patients with active Cushing's also reported higher levels of somatization and anxiety compared to patients in biochemical remission. Overall, this study provides new insights into complex attention and memory deficits in patients with CS and concern regarding cognitive and emotional issues despite resolution of hypercortisolism. Our study opens several avenues for further exploration.
| S-EPMC7428886 | biostudies-literature
Project description:PurposeImpairment of skeletal muscle mass and strength affects 40-70% of patients with active Cushing's syndrome (CS). Glucocorticoid excess sustains muscle atrophy and weakness, while muscle-specific microRNAs (myomiRs) level changes were associated with muscle organization and function perturbation. The aim of the current study is to explore changes in circulating myomiRs in CS patients compared to healthy controls and their involvement in IGFI/PI3K/Akt/mTOR pathway regulation in skeletal muscle.MethodsC2C12, mouse myocytes, were exposed to hydrocortisone (HC), and atrophy-related gene expression was investigated by RT-qPCR, WB and IF to assess HC-mediated atrophic signalling. miRNAs were evaluated in HC-treated C2C12 by PCR Arrays. MyomiRs significantly overexpressed in C2C12 were investigated in 37 CS patients and 24 healthy controls serum by RT-qPCR. The anti-anabolic role of circulating miRNAs significantly upregulated in CS patients was explored in C2C12 by investigating the IGFI/PI3K/Akt/mTOR pathway regulation.ResultsHC induced higher expression of atrophy-related genes, miR-133a-3p, miR-122-5p and miR-200b-3p in C2C12 compared to untreated cells. Conversely, the anabolic IGFI/PI3K/Akt/mTOR signalling was reduced and this effect was mediated by miR-133a-3p. In CS patients miR-133a-3p and miR-200b-3p revealed higher circulating levels (p < 0.0001, respectively) compared to controls. ROC curves for miR-133a-3p (AUC 0.823, p < 0.0001) and miR-200b-3p (AUC 0.850, p < 0.0001) demonstrated that both myomiRs represent potential biomarkers to discriminate between CS and healthy subjects. Pearson's correlation analysis revealed that circulating levels of miR-133a-3p are directly correlated with 24 h urinary-free cortisol level (r = 0.468, p = 0.004) in CS patients.ConclusionsHC induces atrophic signals by miR-133a-3p overexpression in mouse myocytes and humans. Circulating miR-133a-3p is promising biomarkers of hypercortisolism.
| S-EPMC10904409 | biostudies-literature