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ARMC5 Variants in PRKAR1A-Mutated Patients Modify Cortisol Levels and Cushing’S Syndrome

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ARMC5 Variants in PRKAR1A-Mutated Patients Modify Cortisol Levels and Cushing’S Syndrome 27 9 Endocrine-Related A G Maria et al. ARMC5 variants in PRKAR1A 27:9 509–517 Cancer mutated patients RESEARCH ARMC5 variants in PRKAR1A-mutated patients modify cortisol levels and Cushing’s syndrome Andrea Gutierrez Maria1, Christina Tatsi1,2, Annabel Berthon1, Ludivine Drougat1, Nikolaos Settas1, Fady Hannah-Shmouni 1, Jerome Bertherat3, Fabio R Faucz 1 and Constantine A Stratakis1,2 1Section on Endocrinology & Genetics (SEGEN), National Institutes of Health (NIH), Bethesda, Maryland, USA 2Pediatric Endocrinology Inter-Institute Training Program, Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), Bethesda, Maryland, USA 3Service d’Endocrinologie, Hôpital Cochin, APHP, Institut Cochin, INSERM U1016, Université de Paris, Paris, France Correspondence should be addressed to A G Maria: [email protected] Abstract Mutations in the protein kinase A (PKA) regulatory subunit type 1A (PRKAR1A) and Key Words armadillo repeat-containing 5 (ARMC5) genes cause Cushing‘s syndrome (CS) due to f cortisol primary pigmented nodular adrenocortical disease (PPNAD) and primary bilateral f adrenocortical hyperplasia macronodular adrenocortical hyperplasia (PBMAH), respectively. Between the two genes, f PRKAR1A gene ARMC5 is highly polymorphic with several variants in the population, whereas PRKAR1A f ARMC5 gene has very little, if any, non-pathogenic variation in its coding sequence. We tested the hypothesis that ARMC5 variants may affect the clinical presentation of PPNAD and CS among patients with PRKAR1A mutations. In this study, 91 patients with PPNAD due to PRKAR1A mutations were tested for abnormal cortisol secretion or CS and for ARMC5 sequence variants. Abnormal cortisol secretion was present in 71 of 74 patients with ARMC5 variants, whereas 11 of 17 patients negative for ARMC5 variants did not have hypercortisolemia. The presence of ARMC5 variants was a statistically strong predictor of CS among patients with PRKAR1A mutations (P < 0.001). Among patients with CS due to PPNAD, ARMC5 variants were associated with lower cortisol levels at baseline (P = 0.04) and after high dose dexamethasone administration (P = 0.02). The ARMC5 p.I170V variant increased ARMC5 protein accumulation in vitro and decreased viability of NCI-H295 cells (but not HEK 293T cells). PPNAD tissues with ARMC5 variants showed stronger ARMC5 protein expression than those that carried a normal ARMC5 sequence. Taken together, our results suggest that ARMC5 variants among patients with PPNAD due to PRKAR1A defects may play the role of a genetic modifier for the presence and severity of hypercortisolemia. Endocrine-Related Cancer (2020) 27, 509–517 Introduction Cyclic adenosine monophosphate (cAMP)-dependent and RIIβ) and four C-subunits (Cα, Cβ, and Cγ, and PRKX); protein kinase or PKA mediates most cAMP-signaling in each are coded by their own genes (PRKAR1A, PRKAR1B, the adrenal cortex through its regulatory (R) and catalytic PRKAR2A, PRKAR2B, PRKACA, PRKACB, PRKACG, and (C) subunits (Almeida & Stratakis 2011, de Joussineau et al. PRKAX, respectively) (Almeida & Stratakis 2011). RIα, Cα 2012). There are four different R-subunits (RIα, RIβ, RIIα and Cβ defects have been implicated in corticotrophin https://erc.bioscientifica.com © 2020 Society for Endocrinology https://doi.org/10.1530/ERC-20-0273 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 10/02/2021 05:03:31PM via free access -20-0273 Endocrine-Related A G Maria et al. ARMC5 variants in PRKAR1A 27:9 510 Cancer mutated patients (ACTH)-independent, adrenocortical Cushing‘s syndrome may also lead to CS of varying degrees of severity: PPNAD (CS) (Stratakis 2014, Espiard et al. 2018, Hannah-Shmouni can be insidious or lead to early onset, pediatric CS (Sarlis & Stratakis 2020). PRKAR1A mutations cause Carney et al. 1997, Pereira et al. 2010, Lowe et al. 2017). Like complex (CNC), a rare multiple neoplasia syndrome CTNNB1 (Tadjine et al. 2008) and PDE11A (Libé et al. 2011) inherited in an autosomal dominant manner (Kirschner defects in the past, in this study, we tested the hypothesis et al. 2000, Horvath et al. 2010), manifesting with primary that ARMC5 variants may play a role in the adrenocortical pigmented nodular adrenocortical disease (PPNAD), as expression of a PRKAR1A-inactivating mutation, causative well as (rarely) cortisol-producing adenomas (CPA) causing of PPNAD and CS. The data suggest that ARMC5 may have CS (Bertherat et al. 2003, 2009). The importance of the a role in modifying cortisol secretion in PPNAD. role of cAMP-signaling for adrenocortical function and regulation of cortisol secretion was further enhanced by the discovery of cAMP-phosphodiesterase 11 A (PDE11A) defects in association with PPNAD and PPNAD-like lesions Materials and methods and CS (Horvath et al. 2006). Clinical and DNA studies cAMP-signaling defects and abnormal PKA activity have also been implicated in another form of adrenocortical Patients were evaluated at the NIH Clinical Center CS, primary bilateral macronodular adrenocortical between 1995 and 2020 under protocol 95-CH-0059. hyperplasia (PBMAH) (Bourdeau et al. 2006, Almeida et al. Ethics approval was granted from the Institutional Review 2011, 2012). In both PPNAD and PBMAH, regardless of Boards of the Eunice Kennedy Shriver National Institute the underlying primary defect, other genes or pathways of Child Health and Human Development (NICHD) appear to play a modifier role in the clinical phenotype (until 2010) and the National Institute of Diabetes and of the affected patients and/or the onset and severity of Digestive and Kidney Diseases (NIDDK) (2010 to present), hypercortisolemia and CS. For example, somatic CTNNB1 NIH (Clinical Trial Registration no. NCT00001452). For mutations have been described in patients with PRKAR1A all patients, informed consents were obtained; assents defects that present with a CPA in addition to PPNAD were signed by minors and consents obtained from their and severe CS (Tadjine et al. 2008). Furthermore, PDE11A parents, as appropriate. variants may increase the severity of CS in PPNAD (Libé A total of 91 patients with CNC and PPNAD who were et al. 2011) and participate in the pathogenesis of other evaluated for hypercortisolemia and CS and were older adrenocortical lesions, from PBMAH to CPAs, and possibly than 20 years of age at the time of the last follow-up or had adrenocortical cancer (Libé et al. 2008, Vezzosi et al. 2012). already developed CS were included in the study. Patients Mutations of the armadillo repeat-containing 5 were initially examined for clinical features of CNC per (ARMC5) gene are the main causative genetic defect of established guidelines (Stratakis & Raygada 1993). The PBMAH (Assié et al. 2013, Faucz et al. 2014), although biochemical diagnosis of hypercortisolemia relied upon others exist too, from GNAS1 to MEN1 and GIPR (Hsiao elevations in 24-h urinary-free cortisol (UFC) above et al. 2009, Lecoq et al. 2017). In addition to PDE11A (Libé the upper cutoffs of reference intervals; loss of diurnal et al. 2008, Vezzosi et al. 2012), it has long been suspected circadian rhythm in midnight salivary cortisol; and lack that additional genes or pathways (Bourdeau et al. 2004, of suppression or a paradoxical response of serum cortisol Bimpaki et al. 2010) may modify the phenotype of CS following the overnight high dose dexamethasone among patients with PBMAH that can be very variable, suppression test, as detailed elsewhere (Stratakis & from asymptomatic to cyclical and, less frequently, severe Raygada 1993, Stratakis et al. 1999, Tirosh et al. 2016). CS (Hsiao et al. 2009). Yet, little is known about the newly ACTH-independent hypercortisolemia was ascertained identified ARMC5 gene and its possible interactions through ACTH measurement, second-tier biochemical or regulators. testing and radiographic imaging. Tumor samples were The highly polymorphic ARMC5 gene in the general obtained from patients, as previously described (Bertherat population is widely expressed in human tissues, et al. 2003, Horvath et al. 2006). particularly in the adrenal cortex (Berthon et al. 2017a). DNA was extracted from peripheral blood and fresh- Conversely, PRKAR1A is also ubiquitously expressed but, frozen tissues, as previously described (Kirschner et al. unlike ARMC5, does not have frequent coding variants 2000, Bertherat et al. 2009, Horvath et al. 2010, Libé et al. in the general population (Bertherat et al. 2009, Horvath 2011). Sequencing for PRKAR1A and ARMC5 genes was et al. 2010). Hypercortisolemia due to PRKAR1A defects obtained, as described elsewhere (Kirschner et al. 2000, https://erc.bioscientifica.com © 2020 Society for Endocrinology https://doi.org/10.1530/ERC-20-0273 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 10/02/2021 05:03:31PM via free access Endocrine-Related A G Maria et al. ARMC5 variants in PRKAR1A 27:9 511 Cancer mutated patients Bertherat et al. 2009, Horvath et al. 2010, Assié et al. 2013, Analysis of protein expression in vitro Faucz et al. 2014). The coding and the flanking intronic HEK 293T and NCI-H295 cells were seeded into six-well sequences were sequenced for both genes. plates at a density of 3 × 105 and 5 × 105 cells per well, respectively. After 24 h of incubation, HEK 293T cells In silico modeling were transfected with Lipofectamine 2000 (11668030, Invitrogen) using Opti-MEM I Reduced Serum Medium Germline variants in ARMC5
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