{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T12:17:21Z","timestamp":1790252241198,"version":"4.1.0"},"reference-count":51,"publisher":"The Endocrine Society","issue":"12","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2005,12,1]]},"abstract":"<jats:p>Congenital hypothyroidism with thyroid dysgenesis (TD) is a frequent human condition characterized by elevated levels of TSH in response to reduced thyroid hormone levels. Congenital hypothyroidism is a genetically heterogeneous disease. In the majority of cases studied, no causative mutations have been identified and very often the disease does not show a Mendelian transmission. However, in approximately 5% of cases, it can be a consequence of mutations in genes encoding the TSH receptor or the transcription factors TITF1, FOXE1, or PAX8. We report here that in mouse models, the combination of partial deficiencies in the Titf1 and Pax8 genes results in an overt TD phenotype that is absent in either of the singly deficient, heterozygous mice. The disease is characterized by a small thyroid gland, elevated levels of TSH, reduced thyroglobulin biosynthesis, and high occurrence of hemiagenesis. The observed phenotype is strain specific, and the pattern of transmission indicates that at least two other genes, in addition to Titf1 and Pax8, are necessary to generate the condition. These results show that TD can be of multigenic origin in mice and strongly suggest that a similar pathogenic mechanism may be observed in humans.<\/jats:p>","DOI":"10.1210\/en.2005-0882","type":"journal-article","created":{"date-parts":[[2005,9,8]],"date-time":"2005-09-08T20:43:34Z","timestamp":1126212214000},"page":"5038-5047","source":"Crossref","is-referenced-by-count":103,"title":["A Mouse Model Demonstrates a Multigenic Origin of Congenital Hypothyroidism"],"prefix":"10.1210","volume":"146","author":[{"given":"Elena","family":"Amendola","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pasquale","family":"De Luca","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo Emidio","family":"Macchia","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Terracciano","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annamaria","family":"Rosica","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gennaro","family":"Chiappetta","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shioko","family":"Kimura","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed","family":"Mansouri","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Affuso","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudio","family":"Arra","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenzo","family":"Macchia","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Di Lauro","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"De Felice","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","reference":[{"key":"2020071612381101000_R1","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1056\/NEJM198103193041205","article-title":"Thyroid development and disorders of thyroid function in the newborn.","volume":"304","author":"Fisher","year":"1981","journal-title":"N Engl J Med"},{"key":"2020071612381101000_R2","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1210\/er.2003-0028","article-title":"Thyroid development and its disorders: genetics and molecular mechanisms.","volume":"25","author":"De Felice","year":"2004","journal-title":"Endocr Rev"},{"key":"2020071612381101000_R3","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1136\/jmg.2004.024158","article-title":"Genetics of congenital hypothyroidism.","volume":"42","author":"Park","year":"2005","journal-title":"J Med Genet"},{"key":"2020071612381101000_R4","doi-asserted-by":"crossref","first-page":"4072","DOI":"10.1210\/jc.2001-011995","article-title":"Discordance of monozygotic twins for thyroid dysgenesis: implications for screening and for molecular pathophysiology.","volume":"87","author":"Perry","year":"2002","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071612381101000_R5","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1056\/NEJM199501193320305","article-title":"Brief report: resistance to thyrotropin caused by mutations in the thyrotropin-receptor gene.","volume":"332","author":"Sunthornthepvarakui","year":"1995","journal-title":"N Engl J Med"},{"key":"2020071612381101000_R6","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1007\/BF03347364","article-title":"Resistance to thyrotropin.","volume":"26","author":"Refetoff","year":"2003","journal-title":"J Endocrinol Invest"},{"key":"2020071612381101000_R7","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1172\/JCI0214341","article-title":"Choreoathetosis, hypothyroidism, and pulmonary alterations due to human NKX2\u20131 haploinsufficiency.","volume":"109","author":"Krude","year":"2002","journal-title":"J Clin Invest"},{"key":"2020071612381101000_R8","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1172\/JCI0214192","article-title":"Partial deficiency of thyroid transcription factor 1 produces predominantly neurological defects in humans and mice.","volume":"109","author":"Pohlenz","year":"2002","journal-title":"J Clin Invest"},{"key":"2020071612381101000_R9","doi-asserted-by":"crossref","first-page":"2295","DOI":"10.1210\/me.2003-0175","article-title":"Hypothyroidism in thyroid transcription factor 1 haploinsufficiency is caused by reduced expression of the thyroid stimulating hormone receptor.","volume":"17","author":"Moeller","year":"2003","journal-title":"Mol Endocrinol"},{"key":"2020071612381101000_R10","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.jpeds.2004.04.011","article-title":"Autosomal dominant transmission of congenital hypothyroidism, neonatal respiratory distress, and ataxia caused by a mutation of NKX2\u20131.","volume":"145","author":"Doyle","year":"2004","journal-title":"J Pediatr"},{"key":"2020071612381101000_R11","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1038\/ng0598-83","article-title":"PAX8 mutations associated with congenital hypothyroidism caused by thyroid dysgenesis.","volume":"19","author":"Macchia","year":"1998","journal-title":"Nat Genet"},{"key":"2020071612381101000_R12","first-page":"234","article-title":"Autosomal dominant transmission of congenital thyroid hypoplasia due to loss-of-function mutation of PAX8.","volume":"86","author":"Vilain","year":"2001","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071612381101000_R13","doi-asserted-by":"crossref","first-page":"3962","DOI":"10.1210\/jcem.86.8.7765","article-title":"A novel mutation (Q40P) in PAX8 associated with congenital hypothyroidism and thyroid hypoplasia: evidence for phenotypic variability in mother and child.","volume":"86","author":"Congdon","year":"2001","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071612381101000_R14","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1067\/mpd.2001.117071","article-title":"Thyroid dysgenesis caused by PAX8 mutation: the hypermutability with CpG dinucleotides at codon 31.","volume":"139","author":"Komatsu","year":"2001","journal-title":"J Pediatr"},{"key":"2020071612381101000_R15","doi-asserted-by":"crossref","first-page":"4285","DOI":"10.1210\/jc.2004-0166","article-title":"Characterization of a novel loss of function mutation of PAX8 in a familial case of congenital hypothyroidism with in-place, normal-sized thyroid.","volume":"89","author":"Meeus","year":"2004","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071612381101000_R16","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1038\/1294","article-title":"Mutation of the gene encoding human TTF-2 associated with thyroid agenesis, cleft palate and choanal atresia.","volume":"19","author":"Clifton-Bligh","year":"1998","journal-title":"Nat Genet"},{"key":"2020071612381101000_R17","doi-asserted-by":"crossref","first-page":"2051","DOI":"10.1093\/hmg\/11.17.2051","article-title":"A novel loss-of-function mutation in TTF-2 is associated with congenital hypothyroidism, thyroid agenesis and cleft palate.","volume":"11","author":"Castanet","year":"2002","journal-title":"Hum Mol Genet"},{"key":"2020071612381101000_R18","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1038\/sj.ejhg.5201321","article-title":"Linkage and mutational analysis of familial thyroid dysgenesis suggest genetic heterogeneity.","volume":"13","author":"Castanet","year":"2005","journal-title":"Eur J Hum Genet"},{"key":"2020071612381101000_R19","doi-asserted-by":"crossref","first-page":"2009","DOI":"10.1210\/jcem.86.5.7501","article-title":"Nineteen years of national screening for congenital hypothyroidism: familial cases with thyroid dysgenesis suggest the involvement of genetic factors.","volume":"86","author":"Castanet","year":"2001","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071612381101000_R20","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1056\/NEJM200008103430614","article-title":"Familial forms of thyroid dysgenesis among infants with congenital hypothyroidism.","volume":"343","author":"Castanet","year":"2000","journal-title":"N Engl J Med"},{"key":"2020071612381101000_R21","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1210\/jcem.87.2.8268","article-title":"Thyroid developmental anomalies in first degree relatives of children with congenital hypothyroidism.","volume":"87","author":"Leger","year":"2002","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071612381101000_R22","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1089\/thy.1999.9.1075","article-title":"Thyroid hemiagenesis in an endemic goiter area diagnosed by ultrasonography: report of sixteen patients.","volume":"9","author":"Mikosch","year":"1999","journal-title":"Thyroid"},{"key":"2020071612381101000_R23","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1101\/gad.10.1.60","article-title":"The T\/ebp null mouse: thyroid-specific enhancer-binding protein is essential for the organogenesis of the thyroid, lung, ventral forebrain, and pituitary.","volume":"10","author":"Kimura","year":"1996","journal-title":"Genes Dev"},{"key":"2020071612381101000_R24","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1038\/ng0598-87","article-title":"Follicular cells of the thyroid gland require Pax8 gene function.","volume":"19","author":"Mansouri","year":"1998","journal-title":"Nat Genet"},{"key":"2020071612381101000_R25","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1016\/j.ydbio.2004.08.048","article-title":"An integrated regulatory network controlling survival and migration in thyroid organogenesis.","volume":"276","author":"Parlato","year":"2004","journal-title":"Dev Biol"},{"key":"2020071612381101000_R26","doi-asserted-by":"crossref","first-page":"15462","DOI":"10.1073\/pnas.242328999","article-title":"Role of the thyroid-stimulating hormone receptor signaling in development and differentiation of the thyroid gland.","volume":"99","author":"Postiglione","year":"2002","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071612381101000_R27","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":"Chomczynski","year":"1987","journal-title":"Anal Biochem"},{"key":"2020071612381101000_R28","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the false discovery rate: a practical and powerful approach to multiple testing.","volume":"57","author":"Benjamini","year":"1995","journal-title":"J R Stat Soc B"},{"key":"2020071612381101000_R29","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/S0079-6603(00)66033-6","article-title":"A unique combination of transcription factors controls differentiation of thyroid cells.","volume":"66","author":"Damante","year":"2001","journal-title":"Prog Nucleic Acid Res Mol Biol"},{"key":"2020071612381101000_R30","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1159\/000022939","article-title":"A complete enumeration and classification of two-locus disease models.","volume":"50","author":"Li","year":"2000","journal-title":"Hum Hered"},{"key":"2020071612381101000_R31","doi-asserted-by":"crossref","first-page":"26649","DOI":"10.1074\/jbc.270.44.26649","article-title":"Redundant domains contribute to the transcriptional activity of Thyroid Transcription Factor 1 (TTF-1).","volume":"270","author":"De Felice","year":"1995","journal-title":"J Biol Chem"},{"key":"2020071612381101000_R32","doi-asserted-by":"crossref","first-page":"4230","DOI":"10.1128\/MCB.12.9.4230","article-title":"Pax-8, a paired domain-containing protein, binds to a sequence overlapping the recognition site of a homeodomain and activates transcription from two thyroid-specific promoters.","volume":"12","author":"Zannini","year":"1992","journal-title":"Mol Cell Biol"},{"key":"2020071612381101000_R33","doi-asserted-by":"crossref","first-page":"2051","DOI":"10.1128\/MCB.19.3.2051","article-title":"The paired-domain transcription factor Pax8 binds to the upstream enhancer of the rat sodium\/iodide symporter gene and participates in both thyroid-specific and cyclic-AMP-dependent transcription.","volume":"19","author":"Ohno","year":"1999","journal-title":"Mol Cell Biol"},{"key":"2020071612381101000_R34","doi-asserted-by":"crossref","first-page":"3395","DOI":"10.1074\/jbc.M205977200","article-title":"The paired domain-containing factor Pax8 and the homeodomain-containing factor TTF-1 directly interact and synergistically activate transcription.","volume":"278","author":"Di Palma","year":"2003","journal-title":"J Biol Chem"},{"key":"2020071612381101000_R35","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1038\/nrg1576","article-title":"Strategies for mapping and cloning quantitative trait genes in rodents.","volume":"6","author":"Flint","year":"2005","journal-title":"Nat Rev Genet"},{"key":"2020071612381101000_R36","doi-asserted-by":"crossref","first-page":"2549","DOI":"10.1210\/jcem.87.6.8536","article-title":"Germline mutations of TSH receptor gene as cause of nonautoimmune subclinical hypothyroidism.","volume":"87","author":"Alberti","year":"2002","journal-title":"J Clin Endocrinol Metab 2002"},{"key":"2020071612381101000_R37","doi-asserted-by":"crossref","first-page":"1534","DOI":"10.1210\/jc.2002-021574","article-title":"Thyroid hemiagenesis: prevalence in normal children and effect on thyroid function.","volume":"88","author":"Maiorana","year":"2003","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071612381101000_R38","doi-asserted-by":"crossref","first-page":"1309","DOI":"10.1210\/jcem-26-12-1309","article-title":"Thyroid dysgenesis in two pairs of monozygotic twins and in a mother and child.","volume":"26","author":"Greig","year":"1966","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071612381101000_R39","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1007\/BF03351023","article-title":"Thyroid hemiagenesis in two sisters.","volume":"7","author":"Rajmil","year":"1984","journal-title":"J Endocrinol Invest"},{"key":"2020071612381101000_R40","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1136\/adc.55.8.639","article-title":"Familial thyroid ectopy and hemiagenesis.","volume":"55","author":"Rosenberg","year":"1980","journal-title":"Arch Dis Child"},{"key":"2020071612381101000_R41","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1007\/BF00251309","article-title":"Thyroid dysgenesis in monozygotic twins: variants identified by scintigraphy.","volume":"10","author":"McLean","year":"1985","journal-title":"Eur J Nucl Med"},{"key":"2020071612381101000_R42","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1203\/01.PDR.0000161409.04177.36","article-title":"Thyroid hemiagenesis is a rare variant of thyroid dysgenesis with a familial component but without Pax8 mutations in a cohort of 22 cases.","volume":"57","author":"Castanet","year":"2005","journal-title":"Pediatr Res"},{"key":"2020071612381101000_R43","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1002\/ajmg.a.20609","article-title":"New case of thyroid dysgenesis and clinical signs of hypothyroidism in Williams syndrome.","volume":"127","author":"Bini","year":"2004","journal-title":"Am J Med Genet A"},{"key":"2020071612381101000_R44","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1097\/00019605-200310000-00011","article-title":"Thyroid hypoplasia of the left lobe in two girls affected by Williams syndrome.","volume":"12","author":"Stagi","year":"2003","journal-title":"Clin Dysmorphol"},{"key":"2020071612381101000_R45","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1002\/(SICI)1096-8628(19990827)85:5<491::AID-AJMG11>3.0.CO;2-Z","article-title":"Thyroid hemiagenesis and elevated thyrotropin levels in a child with Williams syndrome.","volume":"85","author":"Cammareri","year":"1999","journal-title":"Am J Med Genet"},{"key":"2020071612381101000_R46","doi-asserted-by":"crossref","first-page":"1989","DOI":"10.1242\/dev.121.7.1989","article-title":"The role of Hoxa-3 in mouse thymus and thyroid development.","volume":"121","author":"Manley","year":"1995","journal-title":"Development"},{"key":"2020071612381101000_R47","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1006\/dbio.1997.8827","article-title":"Hox group 3 paralogs regulate the development and migration of the thymus, thyroid, and parathyroid glands.","volume":"195","author":"Manley","year":"1998","journal-title":"Dev Biol"},{"key":"2020071612381101000_R48","doi-asserted-by":"crossref","first-page":"1865","DOI":"10.1016\/S0002-9440(10)63745-5","article-title":"Genetic deletion of sonic hedgehog causes hemiagenesis and ectopic development of the thyroid in mouse.","volume":"164","author":"Fagman","year":"2004","journal-title":"Am J Pathol"},{"key":"2020071612381101000_R49","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1002\/dvdy.10325","article-title":"Perturbed thyroid morphology and transient hypothyroidism symptoms in Hoxa5 mutant mice.","volume":"227","author":"Meunier","year":"2003","journal-title":"Dev Dyn"},{"key":"2020071612381101000_R50","doi-asserted-by":"crossref","first-page":"3209","DOI":"10.1210\/jcem.87.7.8662","article-title":"Subclinical hypothyroidism in early childhood: a frequent outcome of transient neonatal hyperthyrotropinemia.","volume":"87","author":"Calaciura","year":"2002","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071612381101000_R51","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1507\/endocrj.50.409","article-title":"Thyroid hemiagenesis with multinodular goiter: a case report and review of the literature.","volume":"50","author":"Karabay","year":"2003","journal-title":"Endocr J"}],"container-title":["Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/146\/12\/5038\/9020901\/endo5038.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/146\/12\/5038\/9020901\/endo5038.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,3]],"date-time":"2025-01-03T18:57:56Z","timestamp":1735930676000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/endo\/article\/146\/12\/5038\/2499826"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2005,12,1]]},"references-count":51,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2005,12,1]]}},"URL":"https:\/\/doi.org\/10.1210\/en.2005-0882","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.723615966.793503203","asserted-by":"object"}]},"ISSN":["0013-7227","1945-7170"],"issn-type":[{"value":"0013-7227","type":"print"},{"value":"1945-7170","type":"electronic"}],"subject":[],"published":{"date-parts":[[2005,12,1]]}}}