{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T05:25:17Z","timestamp":1783488317857,"version":"3.55.0"},"reference-count":49,"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: Heterozygous mutations in thyroid hormone receptor-\u03b2 (TR\u03b2) gene are the cause of resistance to thyroid hormone (RTH) in more than 85% of families having the syndrome. In 23% of the families, TR\u03b2 gene mutations occur de novo. Of the 141 families with RTH investigated by us, 21 (15%) had no TR\u03b2 gene mutations detectable by sequencing from genomic DNA (gDNA) or cDNA (non-TR RTH).<\/jats:p>\n               <jats:p>Objective: The objective of the study was to investigate the genotype of a family with RTH and correlate it to the phenotype.<\/jats:p>\n               <jats:p>Design: The DNA was isolated from different tissues, and the sequence of the TR\u03b2 gene was determined. Clinical studies involved the administration of incremental doses of T3.<\/jats:p>\n               <jats:p>Setting: The study was conducted at a referral pediatric endocrinology clinic in Turkey and an academic medical center in the United States.<\/jats:p>\n               <jats:p>Main Outcome and Measures: Measurement included markers of thyroid hormone action and sequencing of TR\u03b2 revealing a R338W mutation.<\/jats:p>\n               <jats:p>Patients and Family: We studied two siblings with short stature, panic disorder, psychosis, and high free iodothyronine concentrations with nonsuppressed TSH and their father with similar thyroid function tests without growth or psychiatric abnormalities.<\/jats:p>\n               <jats:p>Results: Direct sequencing of gDNA obtained from the father\u2019s leukocytes, buccal mucosa cells, and prostate tissue showed less amplification of the mutant allele (R338W) than the normal allele as confirmed by PCR\/restriction fragment length polymorphism analysis. No sequence abnormalities were detected in gDNA from fibroblasts. Similar results were found in mRNA from the leukocytes and fibroblasts. The sensitivity of various tissues to thyroid hormone was not uniform. The progeny had equal amounts of mutant and wild-type gDNA in leukocytes and skin.<\/jats:p>\n               <jats:p>Conclusions: The father has a mosaicism for the R338W mutation as it was present in some cell lineages, including his germline, because it was transferred to his children but not in fibroblasts. This indicates that the mutation occurred de novo in early embryonic life. Here is the first report of mosaicism in RTH. The possibility of mosaicism should be considered in subjects with RTH without apparent mutations in the TR\u03b2 gene.<\/jats:p>","DOI":"10.1210\/jc.2006-0727","type":"journal-article","created":{"date-parts":[[2006,6,28]],"date-time":"2006-06-28T01:38:01Z","timestamp":1151458681000},"page":"3471-3477","source":"Crossref","is-referenced-by-count":44,"title":["Mosaicism of a Thyroid Hormone Receptor-\u03b2 Gene Mutation in Resistance to Thyroid Hormone"],"prefix":"10.1210","volume":"91","author":[{"given":"Sunee","family":"Mamanasiri","sequence":"first","affiliation":[{"name":"Departments of Medicine (S.M., A.M.D., X.-H.L., R.E.W., S.R.) TR-35240 Izmir, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sena","family":"Yesil","sequence":"additional","affiliation":[{"name":"Division of Endocrinology (S.Y., T.D.), Dokuz Eylu\u0308l University, TR-35240 Izmir, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra M.","family":"Dumitrescu","sequence":"additional","affiliation":[{"name":"Departments of Medicine (S.M., A.M.D., X.-H.L., R.E.W., S.R.) TR-35240 Izmir, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Hui","family":"Liao","sequence":"additional","affiliation":[{"name":"Departments of Medicine (S.M., A.M.D., X.-H.L., R.E.W., S.R.) TR-35240 Izmir, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tevfik","family":"Demir","sequence":"additional","affiliation":[{"name":"Division of Endocrinology (S.Y., T.D.), Dokuz Eylu\u0308l University, TR-35240 Izmir, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roy E.","family":"Weiss","sequence":"additional","affiliation":[{"name":"Departments of Medicine (S.M., A.M.D., X.-H.L., R.E.W., S.R.) TR-35240 Izmir, Turkey"},{"name":"Molecular Medicine (S.R., R.E.W.), The University of Chicago, Chicago, Illinois 60637"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"Refetoff","sequence":"additional","affiliation":[{"name":"Departments of Medicine (S.M., A.M.D., X.-H.L., R.E.W., S.R.) TR-35240 Izmir, Turkey"},{"name":"Pediatrics (S.R.) TR-35240 Izmir, Turkey"},{"name":"Committees on Genetics (S.R.) TR-35240 Izmir, Turkey"},{"name":"Molecular Medicine (S.R., R.E.W.), The University of Chicago, Chicago, Illinois 60637"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","reference":[{"key":"2020071614242194700_R1","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1210\/jcem-27-2-279","article-title":"Familial syndrome combining deaf-mutism, stuppled epiphyses, goiter and abnormally high PBI: possible target organ refractoriness to thyroid hormone","volume":"27","author":"Refetoff","year":"1967","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071614242194700_R2","first-page":"1109","article-title":"Resistance to thyroid hormone","author":"Refetoff","year":"2005","journal-title":"In: Braverman LE, Utiger RE, eds. Werner and Ingbar\u2019s the thyroid: a fundamental and clinical text. 9th ed. Philadelphia: Lippincott, Williams and Wilkins;"},{"key":"2020071614242194700_R3","first-page":"348","article-title":"The syndrome of resistance to thyroid hormone","volume":"14","author":"Refetoff","year":"1993","journal-title":"Endocr Rev"},{"key":"2020071614242194700_R4","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1089\/thy.1994.4.225","article-title":"The variable clinical phenotype in thyroid hormone resistance syndrome","volume":"4","author":"Beck-Peccoz","year":"1994","journal-title":"Thyroid"},{"key":"2020071614242194700_R5","doi-asserted-by":"crossref","first-page":"572","DOI":"10.7326\/0003-4819-123-8-199510150-00002","article-title":"Genetic and clinical features of 42 kindreds with resistance to thyroid hormone. The National Institute of Health Prospective Study","volume":"123","author":"Brucker-Davis","year":"1995","journal-title":"Ann Intern Med"},{"key":"2020071614242194700_R6","doi-asserted-by":"crossref","first-page":"3246","DOI":"10.1210\/jcem.80.11.7593433","article-title":"Do clinical manifestations of resistance to thyroid hormone correlate with the functional alteration of the corresponding mutant thyroid hormone-\u03b2 receptors?","volume":"80","author":"Hayashi","year":"1995","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071614242194700_R7","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1210\/mend-2-12-1217","article-title":"Tight linkage between the syndrome of generalized thyroid hormone resistance and the human c-erbAb gene","volume":"2","author":"Usala","year":"1988","journal-title":"Mol Endocrinol"},{"key":"2020071614242194700_R8","first-page":"49","article-title":"Recessive inheritance of thyroid hormone resistance caused by complete deletion of the protein-coding region of the thyroid hormone receptor-\u03b2 gene","volume":"74","author":"Takeda","year":"1992","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071614242194700_R9","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1172\/JCI117362","article-title":"Genetic analysis of 29 kindreds with generalized and pituitary resistance to thyroid hormone: identification of thirteen novel mutations in the thyroid hormone receptor \u03b2 gene","volume":"94","author":"Adams","year":"1994","journal-title":"J Clin Invest"},{"key":"2020071614242194700_R10","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1210\/mend.11.4.9914","article-title":"Thyroid hormone resistance syndrome manifests as an aberrant interaction between mutant T3 receptor and transcriptional corepressor","volume":"11","author":"Yoh","year":"1997","journal-title":"Mol Endocrinol"},{"key":"2020071614242194700_R11","doi-asserted-by":"crossref","first-page":"4197","DOI":"10.1210\/endo.139.10.6218","article-title":"Lack of coactivator interaction can be a mechanism for dominant negative activity by mutant thyroid hormone receptors","volume":"139","author":"Liu","year":"1998","journal-title":"Endocrinology"},{"key":"2020071614242194700_R12","first-page":"4196","article-title":"Dominant inheritance of resistance to thyroid hormone not linked to defects in the thyroid hormone receptors \u03b1 or \u03b2 genes may be due to a defective co-factor","volume":"81","author":"Weiss","year":"1996","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071614242194700_R13","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1097\/00060793-200010000-00008","article-title":"Resistance to thyroid hormone in the absence of mutations in the thyroid hormone receptor genes","volume":"7","author":"Sadow","year":"2000","journal-title":"Curr Opin Endocrinol Diabetes"},{"key":"2020071614242194700_R14","first-page":"194","article-title":"Resistance to thyroid hormone in a family with no TR\u03b2 gene anomaly: pathogenic hypotheses","volume":"61","author":"Vlaeminck-Guillem","year":"2000","journal-title":"Ann Endocrinol (Paris)"},{"key":"2020071614242194700_R15","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1089\/105072502753452011","article-title":"Resistance to thyroid hormone in a patient without thyroid hormone receptor mutations","volume":"12","author":"Parikh","year":"2002","journal-title":"Thyroid"},{"key":"2020071614242194700_R16","first-page":"3919","article-title":"Five new families with resistance to thyroid hormone not caused by mutations in the thyroid hormone receptor \u03b2 gene","volume":"84","author":"Pohlenz","year":"1999","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071614242194700_R17","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/0003-2697(87)90021-2","article-title":"Single step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction","volume":"162","author":"Chrmczynski","year":"1987","journal-title":"Anal Biochem"},{"key":"2020071614242194700_R18","first-page":"36","article-title":"Image processing with Image J","volume":"11","author":"Abramoff","year":"2004","journal-title":"Biophotonics Int"},{"key":"2020071614242194700_R19","first-page":"220","article-title":"Identification of eight new mutations in the c-erbAB gene of patients with resistance to thyroid hormone","volume":"62","author":"Margotat","year":"2001","journal-title":"Ann Endocrinol (Paris)"},{"key":"2020071614242194700_R20","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1172\/JCI117376","article-title":"Mutation of CpG dinucleotides located in the triiodothyronine (T3)-binding domain of the thyroid hormone receptor (TR) \u03b2 gene that appears to be devoid of natural mutations may not be detected because they are unlikely to produce the clinical phenotype of resistance to thyroid hormone","volume":"94","author":"Hayashi","year":"1994","journal-title":"J Clin Invest"},{"key":"2020071614242194700_R21","doi-asserted-by":"crossref","first-page":"2408","DOI":"10.1172\/JCI116474","article-title":"Identical mutations in unrelated families with generalized resistance to thyroid hormone occur in cytosine-guanine-rich areas of the thyroid hormone receptor \u03b2 gene: analysis of 15 families","volume":"91","author":"Weiss","year":"1993","journal-title":"J Clin Invest"},{"key":"2020071614242194700_R22","first-page":"1039","article-title":"Correlations of language abnormalities with localization of mutations in the \u03b2-thyroid hormone receptor in 13 kindreds with generalized resistance to thyroid hormone: Identification of four new mutations","volume":"75","author":"Mixon","year":"1992","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071614242194700_R23","first-page":"1254","article-title":"Pituitary resistance to thyroid hormone associated with a base mutation in the hormone-binding domain of the human 3,5,3\u2032-triiodothyronine receptor-\u03b2","volume":"76","author":"Sasaki","year":"1993","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071614242194700_R24","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1111\/j.1365-2265.1993.tb00999.x","article-title":"Identification of a novel mutation in the gene encoding the \u03b2-triiodothyronine receptor in a patient with apparent selective pituitary resistance to thyroid hormone","volume":"38","author":"Mixson","year":"1993","journal-title":"Clin Endocrinol (Oxf)"},{"key":"2020071614242194700_R25","article-title":"Terminal left ventricular failure in a patient with resistance to thyroid hormone","author":"Lazarus"},{"key":"2020071614242194700_R26","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1677\/joe.0.1510293","article-title":"Introducing a point mutation identified in a patient with pituitary resistance to thyroid hormone (Arg 338 to Trp) into other mutant thyroid hormone receptors weakens their dominant negative activities","volume":"151","author":"Ando","year":"1996","journal-title":"J Endocrinol"},{"key":"2020071614242194700_R27","doi-asserted-by":"crossref","first-page":"756","DOI":"10.2169\/internalmedicine.40.756","article-title":"Three Japanese patients from two families with generalized resistance to thyroid hormone with mutations in exon 9 of the thyroid hormone receptor \u03b2 gene","volume":"40","author":"Taniyama","year":"2001","journal-title":"Intern Med"},{"key":"2020071614242194700_R28","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1046\/j.1445-5994.2001.00092.x","article-title":"Chronically elevated thyroid-stimulating hormone: resistance to thyroid hormone","volume":"31","author":"Platts","year":"2001","journal-title":"Intern Med"},{"key":"2020071614242194700_R29","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1007\/BF00276326","article-title":"The mutation spectrum of single base-pair substitutions causing human genetic disease: patterns and predictions","volume":"85","author":"Cooper","year":"1990","journal-title":"Hum Genet"},{"key":"2020071614242194700_R30","doi-asserted-by":"crossref","first-page":"2296","DOI":"10.1172\/JCI116458","article-title":"Differential expression of mutant and normal \u03b2 T3 receptor alleles in kindreds with generalized resistance to thyroid hormone","volume":"91","author":"Mixon","year":"1993","journal-title":"J Clin Invest"},{"key":"2020071614242194700_R31","first-page":"64","article-title":"The relative expression of mutant and normal thyroid hormone receptor genes in patients with generalized resistance to thyroid hormone determined by estimation of their specific messenger ribonucleic acid products","volume":"76","author":"Hayashi","year":"1993","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071614242194700_R32","first-page":"5572","article-title":"Somatic mutation of TR\u03b2 can cause a defect in negative regulation of TSH in a TSH-secreting pituitary tumor","volume":"86","author":"Ando","year":"2001","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071614242194700_R33","doi-asserted-by":"crossref","first-page":"1529","DOI":"10.1210\/mend.15.9.0687","article-title":"Aberrant alternative splicing of thyroid hormone receptor in a TSH-secreting pituitary tumor is a mechanism for hormone resistance","volume":"15","author":"Ando","year":"2001","journal-title":"Mol Endocrinol"},{"key":"2020071614242194700_R34","first-page":"1","article-title":"Multiple etiologies for reduced sensitivity to thyroid hormone","author":"Dumitrescu","year":"2006","journal-title":"Hot Thyroidology (www.hotthyroidology.com);"},{"key":"2020071614242194700_R35","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1086\/380999","article-title":"A novel syndrome combining thyroid and neurological abnormalities is associated with mutations in a monocarboxylate transporter gene","volume":"74","author":"Dumitrescu","year":"2004","journal-title":"Am J Hum Genet"},{"key":"2020071614242194700_R36","doi-asserted-by":"crossref","first-page":"1435","DOI":"10.1016\/S0140-6736(04)17226-7","article-title":"Association between mutations in a thyroid hormone transporter and severe X-linked psychomotor retardation","volume":"364","author":"Friesema","year":"2004","journal-title":"Lancet"},{"key":"2020071614242194700_R37","doi-asserted-by":"crossref","first-page":"1900","DOI":"10.1093\/emboj\/18.7.1900","article-title":"Mice deficient in the steroid receptor coactivator 1 (SRC-1) are resistant to thyroid hormone","volume":"18","author":"Weiss","year":"1999","journal-title":"EMBO J"},{"key":"2020071614242194700_R38","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1172\/JCI9422","article-title":"Thyroid hormone resistance and increased metabolic rate in the RXR-\u03b3-deficient mouse","volume":"106","author":"Brown","year":"2000","journal-title":"J Clin Invest"},{"key":"2020071614242194700_R39","first-page":"3609","article-title":"Search for abnormalities of nuclear corepressors, coactivators and a coregulator in families with resistance to thyroid hormone without mutations in thyroid hormone receptor \u03b2 or \u03b1 genes","volume":"85","author":"Reutrakul","year":"2000","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071614242194700_R40","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1002\/(SICI)1096-8628(19970613)70:3<287::AID-AJMG14>3.0.CO;2-H","article-title":"Mosaicism in pseudoachondroplasia","volume":"70","author":"Ferguson","year":"1997","journal-title":"Am J Med Genet"},{"key":"2020071614242194700_R41","doi-asserted-by":"crossref","first-page":"2265","DOI":"10.1093\/hmg\/6.13.2265","article-title":"Female germline mosaicism in tuberous sclerosis confirmed by molecular genetic analysis","volume":"6","author":"Yates","year":"1997","journal-title":"Hum Mol Genet"},{"key":"2020071614242194700_R42","first-page":"A16","article-title":"Frequent somatic and germline mosaicism in retinoblastoma: relevance to genetic counseling","volume":"61","author":"Sippel","year":"1997","journal-title":"Am J Hum Genet"},{"key":"2020071614242194700_R43","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1136\/jmg.34.11.934","article-title":"Misleading linkage results in an NF2 presymptomatic test owing to mosaicism","volume":"34","author":"Bijlsma","year":"1997","journal-title":"J Med Genet"},{"key":"2020071614242194700_R44","doi-asserted-by":"crossref","first-page":"e32","DOI":"10.1136\/jmg.2003.012369","article-title":"Germline and de novo mutations in the HRPT2 tumour suppressor gene in familial isolated hyperparathyroidism (FIHP)","volume":"41","author":"Villablance","year":"2004","journal-title":"J Med Genet"},{"key":"2020071614242194700_R45","doi-asserted-by":"crossref","first-page":"3674","DOI":"10.1210\/jc.2003-030409","article-title":"Recurrent familial hypocalcemia due to germline mosaicism for an activating mutation of the calcium-sensing receptor gene","volume":"88","author":"Hendy","year":"2003","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071614242194700_R46","doi-asserted-by":"crossref","first-page":"e35","DOI":"10.1136\/jmg.37.11.e35","article-title":"Germline mosaicism for a GNAS1 mutation and Albright hereditary osteodystrophy","volume":"37","author":"Aldred","year":"2000","journal-title":"J Med Genet"},{"key":"2020071614242194700_R47","doi-asserted-by":"crossref","first-page":"3932","DOI":"10.1210\/jc.2004-0568","article-title":"Permanent neonatal diabetes due to paternal germline mosaicism for an activating mutation of the KCNJ11 gene encoding the Kir6.2 subunit of the \u03b2-cell potassium adenosine triphosphate channel","volume":"89","author":"Gloyn","year":"2004","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071614242194700_R48","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1007\/s004390050708","article-title":"Germline mosaicism","volume":"102","author":"Zlotogorn","year":"1998","journal-title":"Hum Genet"},{"key":"2020071614242194700_R49","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1038\/nrg906","article-title":"Mechanisms and consequences of somatic mosaicism in humans","volume":"3","author":"Yossoufian","year":"2002","journal-title":"Nat Rev Genet"}],"container-title":["The Journal of Clinical Endocrinology &amp; Metabolism"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/jcem\/article-pdf\/91\/9\/3471\/9063454\/jcem3471.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/jcem\/article-pdf\/91\/9\/3471\/9063454\/jcem3471.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,7,17]],"date-time":"2020-07-17T02:12:45Z","timestamp":1594951965000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jcem\/article\/91\/9\/3471\/2656625"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2006,9,1]]},"references-count":49,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2006,9,1]]}},"URL":"https:\/\/doi.org\/10.1210\/jc.2006-0727","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]]}}}