{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T12:48:07Z","timestamp":1790426887461,"version":"4.1.0"},"reference-count":0,"publisher":"Bioscientifica","issue":"9","content-domain":{"domain":["erc.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2020,9]]},"abstract":"\n Mutations in the protein kinase A (PKA) regulatory subunit type 1A (\n PRKAR1A<\/jats:italic>\n ) and armadillo repeat-containing 5 (\n ARMC5<\/jats:italic>\n ) genes cause Cushing\u2018s syndrome (CS) due to primary pigmented nodular adrenocortical disease (PPNAD) and primary bilateral macronodular adrenocortical hyperplasia (PBMAH), respectively. Between the two genes,\n ARMC5<\/jats:italic>\n is highly polymorphic with several variants in the population, whereas\n PRKAR1A<\/jats:italic>\n has very little, if any, non-pathogenic variation in its coding sequence. We tested the hypothesis that\n ARMC5<\/jats:italic>\n variants may affect the clinical presentation of PPNAD and CS among patients with\n PRKAR1A<\/jats:italic>\n mutations. In this study, 91 patients with PPNAD due to\n PRKAR1A<\/jats:italic>\n mutations were tested for abnormal cortisol secretion or CS and for\n ARMC5<\/jats:italic>\n sequence variants. Abnormal cortisol secretion was present in 71 of 74 patients with\n ARMC5<\/jats:italic>\n variants, whereas 11 of 17 patients negative for\n ARMC5<\/jats:italic>\n variants did not have hypercortisolemia. The presence of\n ARMC5<\/jats:italic>\n variants was a statistically strong predictor of CS among patients with\n PRKAR1A<\/jats:italic>\n mutations (\n P<\/jats:italic>\n \u2009<\u20090.001). Among patients with CS due to PPNAD,\n ARMC5<\/jats:italic>\n variants were associated with lower cortisol levels at baseline (\n P<\/jats:italic>\n \u2009=\u20090.04) and after high dose dexamethasone administration (\n P<\/jats:italic>\n \u2009=\u20090.02). The\n ARMC5<\/jats:italic>\n p.I170V variant increased ARMC5 protein accumulation in vitro and decreased viability of NCI-H295 cells (but not HEK 293T cells). PPNAD tissues with\n ARMC5<\/jats:italic>\n variants showed stronger ARMC5 protein expression than those that carried a normal\n ARMC5<\/jats:italic>\n sequence. Taken together, our results suggest that\n ARMC5<\/jats:italic>\n variants among patients with PPNAD due to\n PRKAR1A<\/jats:italic>\n defects may play the role of a genetic modifier for the presence and severity of hypercortisolemia.\n <\/jats:p>","DOI":"10.1530\/erc-20-0273","type":"journal-article","created":{"date-parts":[[2020,7,7]],"date-time":"2020-07-07T06:52:28Z","timestamp":1594104748000},"page":"509-517","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-8","source":"Crossref","is-referenced-by-count":11,"title":["ARMC5 variants in PRKAR1A-mutated patients modify cortisol levels and Cushing\u2019s syndrome"],"prefix":"10.1530","volume":"27","author":[{"given":"Andrea Gutierrez","family":"Maria","sequence":"first","affiliation":[{"name":"1Section on Endocrinology & Genetics (SEGEN), National Institutes of Health (NIH), Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Tatsi","sequence":"additional","affiliation":[{"name":"1Section on Endocrinology & Genetics (SEGEN), National Institutes of Health (NIH), Bethesda, Maryland, USA"},{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annabel","family":"Berthon","sequence":"additional","affiliation":[{"name":"1Section on Endocrinology & Genetics (SEGEN), National Institutes of Health (NIH), Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ludivine","family":"Drougat","sequence":"additional","affiliation":[{"name":"1Section on Endocrinology & Genetics (SEGEN), National Institutes of Health (NIH), Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolaos","family":"Settas","sequence":"additional","affiliation":[{"name":"1Section on Endocrinology & Genetics (SEGEN), National Institutes of Health (NIH), Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fady","family":"Hannah-Shmouni","sequence":"additional","affiliation":[{"name":"1Section on Endocrinology & Genetics (SEGEN), National Institutes of Health (NIH), Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerome","family":"Bertherat","sequence":"additional","affiliation":[{"name":"3Service d\u2019Endocrinologie, H\u00f4pital Cochin, APHP, Institut Cochin, INSERM U1016, Universit\u00e9 de Paris, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabio R","family":"Faucz","sequence":"additional","affiliation":[{"name":"1Section on Endocrinology & Genetics (SEGEN), National Institutes of Health (NIH), Bethesda, Maryland, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Constantine A","family":"Stratakis","sequence":"additional","affiliation":[{"name":"1Section on Endocrinology & Genetics (SEGEN), National Institutes of Health (NIH), Bethesda, Maryland, USA"},{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","container-title":["Endocrine-Related Cancer"],"original-title":[],"link":[{"URL":"https:\/\/erc.bioscientifica.com\/view\/journals\/erc\/27\/9\/ERC-20-0273.xml","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/erc.bioscientifica.com\/downloadpdf\/journals\/erc\/27\/9\/ERC-20-0273.xml","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T13:55:46Z","timestamp":1784555746000},"score":1,"resource":{"primary":{"URL":"http:\/\/journals.bioscientifica.com\/erc\/article\/27\/9\/509-517\/25475"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,9]]},"references-count":0,"journal-issue":{"issue":"9"},"URL":"https:\/\/doi.org\/10.1530\/erc-20-0273","relation":{},"ISSN":["1351-0088","1479-6821"],"issn-type":[{"value":"1351-0088","type":"print"},{"value":"1479-6821","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,9]]}}}