{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T11:36:59Z","timestamp":1791286619290,"version":"4.1.0"},"reference-count":33,"publisher":"The Endocrine Society","issue":"9","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2006,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Context: Primary adrenocortical hyperplasias leading to Cushing syndrome include primary pigmented nodular adrenocortical disease and ACTH-independent macronodular adrenal hyperplasia (AIMAH). Inactivating mutations of the 17q22\u201324-located PRKAR1A gene, coding for the type 1A regulatory subunit of protein kinase A (PKA), cause primary pigmented nodular adrenocortical disease and the multiple endocrine neoplasia syndrome Carney complex. PRKAR1A mutations and 17q22\u201324 chromosomal losses have been found in sporadic adrenal tumors and are associated with aberrant PKA signaling.<\/jats:p>\n               <jats:p>Objective: The objective of the study was to examine whether somatic 17q22\u201324 changes, PRKAR1A mutations, and\/or PKA abnormalities are present in AIMAH.<\/jats:p>\n               <jats:p>Patients: We studied fourteen patients with Cushing syndrome due to AIMAH.<\/jats:p>\n               <jats:p>Methods: Fluorescent in situ hybridization with a PRKAR1A-specific probe was used for investigating chromosome 17 allelic losses. The PRKAR1A gene was sequenced in all samples, and tissue was studied for PKA activity, cAMP responsiveness, and PKA subunit expression.<\/jats:p>\n               <jats:p>Results: We found 17q22\u201324 allelic losses in 73% of the samples. There were no PRKAR1A-coding sequence mutations. The RII\u03b2 PKA subunit was overexpressed by mRNA, whereas the RI\u03b1, RI\u03b2, RII\u03b1, and C\u03b1 PKA subunits were underexpressed. These findings were confirmed by immunohistochemistry. Total PKA activity and free PKA activity were higher in AIMAH than normal adrenal glands, consistent with the up-regulation of the RII\u03b2 PKA subunit.<\/jats:p>\n               <jats:p>Conclusions: PRKAR1A mutations are not found in AIMAH. Somatic losses of the 17q22\u201324 region and PKA subunit and enzymatic activity changes show that PKA signaling is altered in AIMAH in a way that is similar to that of other adrenal tumors with 17q losses or PRKAR1A mutations.<\/jats:p>","DOI":"10.1210\/jc.2005-2608","type":"journal-article","created":{"date-parts":[[2006,6,14]],"date-time":"2006-06-14T03:44:19Z","timestamp":1150256659000},"page":"3626-3632","source":"Crossref","is-referenced-by-count":47,"title":["17q22\u201324 Chromosomal Losses and Alterations of Protein Kinase A Subunit Expression and Activity in Adrenocorticotropin-Independent Macronodular Adrenal Hyperplasia"],"prefix":"10.1210","volume":"91","author":[{"given":"Isabelle","family":"Bourdeau","sequence":"first","affiliation":[{"name":"Division of Endocrinology, Department of Medicine (I.B.), Ho\u0302tel-Dieu du Centre Hospitalier de l\u2019Universite\u0301 de Montre\u0301al, Montre\u0301al, Canada QC H2W 1T8"},{"name":"Section on Endocrinology and Genetics (I.B., L.M., S.G.S., F.S., S.B., C.A.S.), Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-1862"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ludmila","family":"Matyakhina","sequence":"additional","affiliation":[{"name":"Section on Endocrinology and Genetics (I.B., L.M., S.G.S., F.S., S.B., C.A.S.), Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-1862"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sotirios G.","family":"Stergiopoulos","sequence":"additional","affiliation":[{"name":"Section on Endocrinology and Genetics (I.B., L.M., S.G.S., F.S., S.B., C.A.S.), Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-1862"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabiano","family":"Sandrini","sequence":"additional","affiliation":[{"name":"Section on Endocrinology and Genetics (I.B., L.M., S.G.S., F.S., S.B., C.A.S.), Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-1862"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sosipatros","family":"Boikos","sequence":"additional","affiliation":[{"name":"Section on Endocrinology and Genetics (I.B., L.M., S.G.S., F.S., S.B., C.A.S.), Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-1862"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Constantine A.","family":"Stratakis","sequence":"additional","affiliation":[{"name":"Section on Endocrinology and Genetics (I.B., L.M., S.G.S., F.S., S.B., C.A.S.), Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-1862"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","reference":[{"key":"2020071614191647800_R1","first-page":"4219","article-title":"Genetic aberrations in adrenocortical tumors detected using comparative genomic hybridization correlate with tumor size and malignancy","volume":"56","author":"Kjellman","year":"1996","journal-title":"Cancer Res"},{"key":"2020071614191647800_R2","doi-asserted-by":"crossref","first-page":"3467","DOI":"10.1210\/jcem.87.7.8697","article-title":"Comparative genomic hybridization analysis of adrenocortical tumors","volume":"87","author":"Sidhu","year":"2002","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071614191647800_R3","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1055\/s-2007-978914","article-title":"Clinical and genetic analysis of primary bilateral adrenal diseases (micro- and macronodular disease) leading to Cushing syndrome","volume":"30","author":"Stratakis","year":"1998","journal-title":"Horm Metab Res"},{"key":"2020071614191647800_R4","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1081\/ERC-200043735","article-title":"Clinical and molecular genetic studies of bilateral adrenal hyperplasias","volume":"30","author":"Bourdeau","year":"2004","journal-title":"Endocr Res"},{"key":"2020071614191647800_R5","doi-asserted-by":"crossref","first-page":"4041","DOI":"10.1210\/jcem.86.9.7903","article-title":"Clinical and molecular features of the Carney complex: diagnostic criteria and recommendations for patient evaluation","volume":"86","author":"Stratakis","year":"2001","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071614191647800_R6","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1038\/79238","article-title":"Mutations of the gene encoding the protein kinase A type I-\u03b1 regulatory subunit in patients with the Carney complex","volume":"26","author":"Kirschner","year":"2000","journal-title":"Nat Genet"},{"key":"2020071614191647800_R7","doi-asserted-by":"crossref","first-page":"3037","DOI":"10.1093\/hmg\/9.20.3037","article-title":"Genetic heterogeneity and spectrum of mutations of the PRKAR1A gene in patients with the Carney complex","volume":"9","author":"Kirschner","year":"2000","journal-title":"Hum Mol Genet"},{"key":"2020071614191647800_R8","doi-asserted-by":"crossref","first-page":"4324","DOI":"10.1210\/jc.2002-020592","article-title":"Mutations of the PRKAR1A gene in Cushing\u2019s syndrome due to sporadic primary pigmented nodular adrenocortical disease","volume":"87","author":"Groussin","year":"2002","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071614191647800_R9","first-page":"5308","article-title":"Molecular and functional analysis of PRKAR1A and its locus (17q22\u201324) in sporadic adrenocortical tumors: 17q losses, somatic mutations, and protein kinase A expression and activity","volume":"63","author":"Bertherat","year":"2003","journal-title":"Cancer Res"},{"key":"2020071614191647800_R10","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1172\/JCI118467","article-title":"Carney complex, a familial multiple neoplasia and lentiginosis syndrome. Analysis of 11 kindreds and linkage to the short arm of chromosome 2","volume":"97","author":"Stratakis","year":"1996","journal-title":"J Clin Invest"},{"key":"2020071614191647800_R11","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1111\/j.1749-6632.2002.tb04339.x","article-title":"Cyclic AMP-dependent signaling aberrations in macronodular adrenal disease","volume":"968","author":"Bourdeau","year":"2002","journal-title":"Ann NY Acad Sci"},{"key":"2020071614191647800_R12","doi-asserted-by":"crossref","first-page":"1688","DOI":"10.1056\/NEJM199112123252403","article-title":"Activating mutations of the stimulatory G protein in the McCune-Albright syndrome","volume":"325","author":"Weinstein","year":"1991","journal-title":"N Engl J Med"},{"key":"2020071614191647800_R13","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1016\/S0022-3476(99)70302-1","article-title":"Cushing\u2019s syndrome caused by nodular adrenal hyperplasia in children with McCune-Albright syndrome","volume":"134","author":"Kirk","year":"1999","journal-title":"J Pediatr"},{"key":"2020071614191647800_R14","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1016\/S0022-3476(05)80943-6","article-title":"Severe endocrine and nonendocrine manifestations of the McCune-Albright syndrome associated with activating mutations of stimulatory G protein GS","volume":"123","author":"Shenker","year":"1993","journal-title":"J Pediatr"},{"key":"2020071614191647800_R15","doi-asserted-by":"crossref","first-page":"2147","DOI":"10.1210\/jc.2002-021362","article-title":"Cushing\u2019s syndrome secondary to adrenocorticotropin-independent macronodular adrenocortical hyperplasia due to activating mutations of GNAS1 gene","volume":"88","author":"Fragoso","year":"2003","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071614191647800_R16","first-page":"75","article-title":"Ectopic and abnormal hormone receptors in adrenal Cushing\u2019s syndrome","volume":"22","author":"Lacroix","year":"2001","journal-title":"Endocr Rev"},{"key":"2020071614191647800_R17","first-page":"3531","article-title":"Are ectopic or abnormal membrane hormone receptors frequently present in adrenal Cushing\u2019s syndrome?","volume":"85","author":"Mircescu","year":"2000","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071614191647800_R18","doi-asserted-by":"crossref","first-page":"851","DOI":"10.3109\/07435809809032696","article-title":"Gastric inhibitory polypeptide (GIP) stimulates cortisol secretion, cAMP production and DNA synthesis in an adrenal adenoma responsible for food-dependent Cushing\u2019s syndrome","volume":"24","author":"Chabre","year":"1998","journal-title":"Endocr Res"},{"key":"2020071614191647800_R19","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1097\/00019616-199901000-00004","article-title":"Clinical evaluation of the presence of abnormal hormone receptors in adrenal Cushing\u2019s syndrome","volume":"9","author":"Lacroix","year":"1999","journal-title":"Endocrinologist"},{"key":"2020071614191647800_R20","first-page":"72","article-title":"Large-scale preparation of sequence-ready bacterial artificial chromosome DNA using QIAGEN columns","volume":"27","author":"Kirschner","year":"1999","journal-title":"Biotechniques"},{"key":"2020071614191647800_R21","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1002\/gcc.10112","article-title":"Regulatory subunit type I-\u03b1 of protein kinase A (PRKAR1A): a tumor-suppressor gene for sporadic thyroid cancer","volume":"35","author":"Sandrini","year":"2002","journal-title":"Genes Chromosomes Cancer"},{"key":"2020071614191647800_R22","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1093\/clinchem\/45.8.1133","article-title":"Optimal temperature selection for mutation detection by denaturing HPLC and comparison to single-stranded conformation polymorphism and heteroduplex analysis","volume":"45","author":"Jones","year":"1999","journal-title":"Clin Chem"},{"key":"2020071614191647800_R23","doi-asserted-by":"crossref","first-page":"1575","DOI":"10.1038\/sj.onc.1207277","article-title":"Gene array analysis of macronodular adrenal hyperplasia confirms clinical heterogeneity and identifies several candidate genes as molecular mediators","volume":"23","author":"Bourdeau","year":"2004","journal-title":"Oncogene"},{"key":"2020071614191647800_R24","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1210\/jc.2005-1301","article-title":"Serial analysis of gene expression in adrenocortical hyperplasia caused by a germline PRKAR1A mutation","volume":"91","author":"Horvath","year":"2006","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071614191647800_R25","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1002\/gcc.20232","article-title":"Molecular and immunohistochemical investigation of protein kinase a regulatory subunit type 1A (PRKAR1A) in odontogenic myxomas","volume":"44","author":"Perdigao","year":"2005","journal-title":"Genes Chromosomes Cancer"},{"key":"2020071614191647800_R26","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1073\/pnas.97.2.835","article-title":"Extracellular protein kinase A as a cancer biomarker: its expression by tumor cells and reversal by a myristate-lacking C\u03b1 and RII\u03b2 subunit overexpression","volume":"97","author":"Cho","year":"2000","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071614191647800_R27","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1136\/jmg.2004.028043","article-title":"A transgenic mouse bearing an antisense construct of regulatory subunit type 1A of protein kinase A develops endocrine and other tumours: comparison with Carney complex and other PRKAR1A induced lesions","volume":"41","author":"Griffin","year":"2004","journal-title":"J Med Genet"},{"key":"2020071614191647800_R28","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1136\/jmg.40.4.268","article-title":"Chromosome 2 (2p16) abnormalities in Carney complex tumours","volume":"40","author":"Matyakhina","year":"2003","journal-title":"J Med Genet"},{"key":"2020071614191647800_R29","first-page":"730","article-title":"Genotyping of adrenocortical tumors: very frequent deletions of the MEN1 locus in 11q13 and of a 1-centimorgan region in 2p16","volume":"84","author":"Kjellman","year":"1999","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071614191647800_R30","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1677\/erc.0.0110265","article-title":"Protein kinase A and its role in human neoplasia: the Carney complex paradigm","volume":"11","author":"Bossis","year":"2004","journal-title":"Endocr Relat Cancer"},{"key":"2020071614191647800_R31","doi-asserted-by":"crossref","first-page":"8811","DOI":"10.1158\/0008-5472.CAN-04-3620","article-title":"Down-regulation of regulatory subunit type 1A of protein kinase A leads to endocrine and other tumors","volume":"64","author":"Griffin","year":"2004","journal-title":"Cancer Res"},{"key":"2020071614191647800_R32","doi-asserted-by":"crossref","first-page":"4506","DOI":"10.1158\/0008-5472.CAN-05-0580","article-title":"A mouse model for the Carney complex tumor syndrome develops neoplasia in cyclic AMP-responsive tissues","volume":"65","author":"Kirschner","year":"2005","journal-title":"Cancer Res"},{"key":"2020071614191647800_R33","first-page":"139","article-title":"Cyclic AMP, PKA, and the physiological regulation of adiposity","volume":"53","author":"McKnight","year":"1998","journal-title":"Rec Prog Horm Res"}],"container-title":["The Journal of Clinical Endocrinology &amp; Metabolism"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/jcem\/article-pdf\/91\/9\/3626\/9065391\/jcem3626.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/jcem\/article-pdf\/91\/9\/3626\/9065391\/jcem3626.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,7,17]],"date-time":"2020-07-17T01:57:01Z","timestamp":1594951021000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jcem\/article\/91\/9\/3626\/2656799"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2006,9,1]]},"references-count":33,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2006,9,1]]}},"URL":"https:\/\/doi.org\/10.1210\/jc.2005-2608","relation":{},"ISSN":["0021-972X","1945-7197"],"issn-type":[{"value":"0021-972X","type":"print"},{"value":"1945-7197","type":"electronic"}],"subject":[],"published":{"date-parts":[[2006,9,1]]}}}