{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T11:42:54Z","timestamp":1747222974216},"reference-count":20,"publisher":"The Endocrine Society","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[1998,3,1]]},"abstract":"<jats:p>Corticotropinomas are characterized by a relative resistance to the negative feedback action of cortisol on ACTH secretion. In this respect there is a similarity with the clinical syndrome of cortisol resistance. As cortisol resistance can be caused by genetic abnormalities in the glucocorticoid receptor (GR) gene, we investigated whether the insensitivity of corticotropinomas to cortisol is also caused by de novo mutations in the GR gene.<\/jats:p>\n               <jats:p>We screened for the GR gene in leukocyte and tumor DNA from 22 patients with Cushing\u2019s disease for mutations using PCR\/single strand conformation polymorphism analysis. In a previous study, we identified 5 polymorphisms in the GR gene in a normal population. These polymorphisms were used as markers for the possible occurrence of loss of heterozygosity (LOH) at the GR gene locus.<\/jats:p>\n               <jats:p>Except for 1 silent point mutation, we did not identify novel mutations in the GR gene in leukocytes or corticotropinomas from these patients. Of the 22 patients, 18 were heterozygous for at least 1 of the polymorphisms. In 6 of these patients, LOH had occurred in the tumor DNA. Of 21 patients examined for LOH on chromosome 11q13, only 1, with a corticotroph carcinoma, showed allelic deletion. As controls we studied 28 pituitary tumors of other subtypes (11 clinically nonfunctioning, 8 prolactinomas, and 9 GH-producing adenomas) and found evidence for LOH in only 1 prolactinoma.<\/jats:p>\n               <jats:p>In six patients LOH was found at the GR gene locus (chromosome 5) in DNA derived from adenoma cells. Our observations indicate for the first time that LOH at the GR gene locus is a relatively frequent phenomenon in pituitary adenomas of patients with Cushing\u2019s disease. This might explain the relative resistance of the adenoma cells to the inhibitory feedback action of cortisol on ACTH secretion. The specificity of the GR LOH to corticotropinomas supports this concept. Somatic mutations of the GR are not a frequent cause of relative cortisol resistance in these cells.<\/jats:p>","DOI":"10.1210\/jcem.83.3.4648","type":"journal-article","created":{"date-parts":[[2014,1,8]],"date-time":"2014-01-08T17:02:57Z","timestamp":1389200577000},"page":"917-921","source":"Crossref","is-referenced-by-count":3,"title":["Human Adrenocorticotropin-Secreting Pituitary Adenomas Show Frequent Loss of Heterozygosity at the Glucocorticoid Receptor Gene Locus1"],"prefix":"10.1210","volume":"83","author":[{"given":"Nannette A. T. M.","family":"Huizenga","sequence":"first","affiliation":[{"name":"Departments of Internal Medicine III (N.A.T.M.H., P.d.L., J.W.K., A.J.v.d.L., F.H.d.J., S.W.J.L.), 3015 GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pieter","family":"de Lange","sequence":"additional","affiliation":[{"name":"Departments of Internal Medicine III (N.A.T.M.H., P.d.L., J.W.K., A.J.v.d.L., F.H.d.J., S.W.J.L.), 3015 GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan W.","family":"Koper","sequence":"additional","affiliation":[{"name":"Departments of Internal Medicine III (N.A.T.M.H., P.d.L., J.W.K., A.J.v.d.L., F.H.d.J., S.W.J.L.), 3015 GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard N.","family":"Clayton","sequence":"additional","affiliation":[{"name":"the Department of Medicine, Keele University (R.N.C., W.E.F.), Stoke on Trent, ST4 7QB United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William E.","family":"Farrell","sequence":"additional","affiliation":[{"name":"the Department of Medicine, Keele University (R.N.C., W.E.F.), Stoke on Trent, ST4 7QB United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aart Jan","family":"van der Lely","sequence":"additional","affiliation":[{"name":"Departments of Internal Medicine III (N.A.T.M.H., P.d.L., J.W.K., A.J.v.d.L., F.H.d.J., S.W.J.L.), 3015 GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Albert O.","family":"Brinkmann","sequence":"additional","affiliation":[{"name":"Endocrinology and Reproduction (A.O.B.), Erasmus University Rotterdam, 3015 GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frank H.","family":"de Jong","sequence":"additional","affiliation":[{"name":"Departments of Internal Medicine III (N.A.T.M.H., P.d.L., J.W.K., A.J.v.d.L., F.H.d.J., S.W.J.L.), 3015 GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven W. J.","family":"Lamberts","sequence":"additional","affiliation":[{"name":"Departments of Internal Medicine III (N.A.T.M.H., P.d.L., J.W.K., A.J.v.d.L., F.H.d.J., S.W.J.L.), 3015 GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"80","reference":[{"key":"2020071619595713500_R1","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1210\/jcem-20-12-1539","article-title":"Tests of pituitary-adrenal suppressibility in the diagnosis of Cushing\u2019s syndrome.","volume":"20","year":"1960","journal-title":"J Clin Enocrinol Metab"},{"key":"2020071619595713500_R2","first-page":"515","article-title":"Oral and intravenous suppression tests in the diagnosis of Cushing\u2019s syndrome.","volume":"33","author":"James","year":"1965","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071619595713500_R3","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1016\/0092-8674(86)90339-9","article-title":"Functional domains of the human 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