{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T10:58:59Z","timestamp":1789210739798,"version":"build-2803163510"},"reference-count":43,"publisher":"The Endocrine Society","issue":"7","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2007,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Dual oxidases generate the hydrogen peroxide needed by thyroid peroxidase for the incorporation of iodine into thyroglobulin, an essential step in thyroid hormone synthesis. Mutations in the human dual oxidase 2 gene, DUOX2, have been shown to underlie several cases of congenital hypothyroidism. We report here the first mouse Duox2 mutation, which provides a new genetic model for studying the specific function of DUOX2 in the thyroid gland and in other organ systems where it is hypothesized to play a role. We mapped the new spontaneous mouse mutation to chromosome 2 and identified it as a T&amp;gt;G base pair change in exon 16 of Duox2. The mutation changes a highly conserved valine to glycine at amino acid position 674 (V674G) and was named \u201cthyroid dyshormonogenesis\u201d (symbol thyd) to signify a defect in thyroid hormone synthesis. Thyroid glands of mutant mice are goitrous and contain few normal follicles, and anterior pituitaries are dysplastic. Serum T4 in homozygotes is about one-tenth the level of controls and is accompanied by a more than 100-fold increase in TSH. The weight of adult mutant mice is approximately half that of littermate controls, and serum IGF-I is reduced. The cochleae of mutant mice exhibit abnormalities characteristic of hypothyroidism, including a delayed formation of the inner sulcus and tunnel of Corti and an abnormally thickened tectorial membrane. Hearing thresholds of adult mutant mice are on average 50\u201360 decibels (dB) above those of controls.<\/jats:p>","DOI":"10.1210\/me.2007-0085","type":"journal-article","created":{"date-parts":[[2007,4,17]],"date-time":"2007-04-17T22:19:13Z","timestamp":1176848353000},"page":"1593-1602","source":"Crossref","is-referenced-by-count":99,"title":["Congenital Hypothyroidism, Dwarfism, and Hearing Impairment Caused by a Missense Mutation in the Mouse Dual Oxidase 2 Gene, Duox2"],"prefix":"10.1210","volume":"21","author":[{"given":"Kenneth R.","family":"Johnson","sequence":"first","affiliation":[{"name":"The Jackson Laboratory, Bar Harbor, Maine 04609"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Coleen C.","family":"Marden","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory, Bar Harbor, Maine 04609"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Ward-Bailey","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory, Bar Harbor, Maine 04609"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leona H.","family":"Gagnon","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory, Bar Harbor, Maine 04609"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roderick T.","family":"Bronson","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory, Bar Harbor, Maine 04609"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leah Rae","family":"Donahue","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory, Bar Harbor, Maine 04609"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","reference":[{"key":"2020071614040389600_R1","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1034\/j.1399-0004.2003.00107.x","article-title":"Development of the thyroid gland: lessons from congenitally hypothyroid mice and men.","volume":"63","author":"Van Vliet","year":"2003","journal-title":"Clin Genet"},{"key":"2020071614040389600_R2","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/S1043-2760(03)00137-1","article-title":"Genetic basis of hypothyroidism: recent advances, gaps and strategies for future research.","volume":"14","author":"Moreno","year":"2003","journal-title":"Trends Endocrinol Metab"},{"key":"2020071614040389600_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":"2020071614040389600_R4","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1126\/science.7209519","article-title":"Inherited primary hypothyroidism in mice.","volume":"212","author":"Beamer","year":"1981","journal-title":"Science"},{"key":"2020071614040389600_R5","first-page":"129","article-title":"Identification of a point mutation in the thyrotropin receptor of the hyt\/hyt hypothyroid mouse.","volume":"8","author":"Stein","year":"1994","journal-title":"Mol Endocrinol"},{"key":"2020071614040389600_R6","doi-asserted-by":"crossref","first-page":"15776","DOI":"10.1073\/pnas.242322099","article-title":"Defining thyrotropin-dependent and -independent steps of thyroid hormone synthesis by using thyrotropin receptor-null mice.","volume":"99","author":"Marians","year":"2002","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071614040389600_R7","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1210\/endo-120-2-838","article-title":"Inherited congenital goiter in mice.","volume":"120","author":"Beamer","year":"1987","journal-title":"Endocrinology"},{"key":"2020071614040389600_R8","doi-asserted-by":"crossref","first-page":"9909","DOI":"10.1073\/pnas.95.17.9909","article-title":"A single amino acid change in the acetylcholinesterase-like domain of thyroglobulin causes congenital goiter with hypothyroidism in the cog\/cog mouse: a model of human endoplasmic reticulum storage diseases.","volume":"95","author":"Kim","year":"1998","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071614040389600_R9","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1093\/hmg\/10.2.153","article-title":"Targeted disruption of mouse Pds provides insight about the inner-ear defects encountered in Pendred syndrome.","volume":"10","author":"Everett","year":"2001","journal-title":"Hum Mol Genet"},{"key":"2020071614040389600_R10","doi-asserted-by":"crossref","first-page":"2584","DOI":"10.1210\/me.2006-0099","article-title":"A novel hypothyroid dwarfism due to the missense mutation Arg479Cys of the thyroid peroxidase gene in the mouse.","volume":"20","author":"Takabayashi","year":"2006","journal-title":"Mol Endocrinol"},{"key":"2020071614040389600_R11","doi-asserted-by":"crossref","first-page":"37265","DOI":"10.1074\/jbc.274.52.37265","article-title":"Purification of a novel flavoprotein involved in the thyroid NADPH oxidase. Cloning of the porcine and human cDNAs.","volume":"274","author":"Dupuy","year":"1999","journal-title":"J Biol Chem"},{"key":"2020071614040389600_R12","doi-asserted-by":"crossref","first-page":"23227","DOI":"10.1074\/jbc.M000916200","article-title":"Cloning of two human thyroid cDNAs encoding new members of the NADPH oxidase family.","volume":"275","author":"De Deken","year":"2000","journal-title":"J Biol Chem"},{"key":"2020071614040389600_R13","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1056\/NEJMoa012752","article-title":"Inactivating mutations in the gene for thyroid oxidase 2 (THOX2) and congenital hypothyroidism.","volume":"347","author":"Moreno","year":"2002","journal-title":"N Engl J Med"},{"key":"2020071614040389600_R14","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1002\/humu.9372","article-title":"Persistent mild hypothyroidism associated with novel sequence variants of the DUOX2 gene in two siblings.","volume":"26","author":"Vigone","year":"2005","journal-title":"Hum Mutat"},{"key":"2020071614040389600_R15","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1051\/rnd:19890401","article-title":"Thyroid hormone and growth: relationships with growth hormone effects and regulation.","volume":"29","author":"Cabello","year":"1989","journal-title":"Reprod Nutr Dev"},{"key":"2020071614040389600_R16","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/S0083-6729(05)71004-9","article-title":"Thyroid hormones and brain development.","volume":"71","author":"Bernal","year":"2005","journal-title":"Vitam Horm"},{"key":"2020071614040389600_R17","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/S0140-6736(73)93310-2","article-title":"Congenital deafness and hypothyroidism.","volume":"2","author":"Deol","year":"1973","journal-title":"Lancet"},{"key":"2020071614040389600_R18","doi-asserted-by":"crossref","first-page":"23","DOI":"10.3109\/00016488609122726","article-title":"Periods of sensitivity to thyroid hormone during the development of the organ of Corti.","volume":"429","author":"Uziel","year":"1986","journal-title":"Acta Otolaryngol Suppl"},{"key":"2020071614040389600_R19","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.mce.2003.11.026","article-title":"Structural and functional characterization of the two human ThOX\/Duox genes and their 5\u2032-flanking regions.","volume":"214","author":"Pachucki","year":"2004","journal-title":"Mol Cell Endocrinol"},{"key":"2020071614040389600_R20","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1101\/gad.875201","article-title":"Proper coronary vascular development and heart morphogenesis depend on interaction of GATA-4 with FOG cofactors.","volume":"15","author":"Crispino","year":"2001","journal-title":"Genes Dev"},{"key":"2020071614040389600_R21","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1101\/gr.3804205","article-title":"Physicochemical constraint violation by missense substitutions mediates impairment of protein function and disease severity.","volume":"15","author":"Stone","year":"2005","journal-title":"Genome Res"},{"key":"2020071614040389600_R22","doi-asserted-by":"crossref","first-page":"30244","DOI":"10.1074\/jbc.M405406200","article-title":"Targeting of the dual oxidase 2 N-terminal region to the plasma membrane.","volume":"279","author":"Morand","year":"2004","journal-title":"J Biol Chem"},{"key":"2020071614040389600_R23","doi-asserted-by":"crossref","first-page":"18269","DOI":"10.1074\/jbc.C600095200","article-title":"Identification of the maturation factor for dual oxidase. Evolution of an eukaryotic operon equivalent.","volume":"281","author":"Grasberger","year":"2006","journal-title":"J Biol Chem"},{"key":"2020071614040389600_R24","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1006\/geno.2001.6586","article-title":"Cloning of tissue-specific genes using serial analysis of gene expression and a novel computational substraction approach.","volume":"75","author":"Moreno","year":"2001","journal-title":"Genomics"},{"key":"2020071614040389600_R25","doi-asserted-by":"crossref","first-page":"4911","DOI":"10.1016\/j.febslet.2005.08.002","article-title":"Differential regulation of dual NADPH oxidases\/peroxidases, Duox1 and Duox2, by Th1 and Th2 cytokines in respiratory tract epithelium.","volume":"579","author":"Harper","year":"2005","journal-title":"FEBS Lett"},{"key":"2020071614040389600_R26","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1152\/physrev.00044.2005","article-title":"The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology.","volume":"87","author":"Bedard","year":"2007","journal-title":"Physiol Rev"},{"key":"2020071614040389600_R27","doi-asserted-by":"crossref","first-page":"1502","DOI":"10.1096\/fj.02-1104fje","article-title":"Dual oxidases represent novel hydrogen peroxide sources supporting mucosal surface host defense.","volume":"17","author":"Geiszt","year":"2003","journal-title":"FASEB J"},{"key":"2020071614040389600_R28","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.1089\/ars.2006.8.1549","article-title":"Role of Nox family NADPH oxidases in host defense.","volume":"8","author":"Leto","year":"2006","journal-title":"Antioxid Redox Signal"},{"key":"2020071614040389600_R29","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1056\/NEJM198803103181003","article-title":"Long-term growth in juvenile acquired hypothyroidism: the failure to achieve normal adult stature.","volume":"318","author":"Rivkees","year":"1988","journal-title":"N Engl J Med"},{"key":"2020071614040389600_R30","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1016\/0092-8674(95)90199-X","article-title":"The nuclear receptor superfamily: the second decade.","volume":"83","author":"Mangelsdorf","year":"1995","journal-title":"Cell"},{"key":"2020071614040389600_R31","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1002\/j.1460-2075.1990.tb08186.x","article-title":"A major thyroid hormone response element in the third intron of the rat growth hormone gene.","volume":"9","author":"Sap","year":"1990","journal-title":"EMBO J"},{"key":"2020071614040389600_R32","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/0378-5955(95)00111-G","article-title":"Hearing loss and cochlear abnormalities in the congenital hypothyroid (hyt\/hyt) mouse.","volume":"88","author":"O\u2019Malley Jr","year":"1995","journal-title":"Hear Res"},{"key":"2020071614040389600_R33","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/S0378-5955(99)00150-1","article-title":"Distortion product otoacoustic emissions and outer hair cell defects in the hyt\/hyt mutant mouse.","volume":"138","author":"Li","year":"1999","journal-title":"Hear Res"},{"key":"2020071614040389600_R34","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1007\/s101620010092","article-title":"Knock-in mouse model for resistance to thyroid hormone (RTH): an RTH mutation in the thyroid hormone receptor beta gene disrupts cochlear morphogenesis.","volume":"3","author":"Griffith","year":"2002","journal-title":"J Assoc Res Otolaryngol"},{"key":"2020071614040389600_R35","doi-asserted-by":"crossref","first-page":"9792","DOI":"10.1523\/JNEUROSCI.21-24-09792.2001","article-title":"Retardation of cochlear maturation and impaired hair cell function caused by deletion of all known thyroid hormone receptors.","volume":"21","author":"Rusch","year":"2001","journal-title":"J Neurosci"},{"key":"2020071614040389600_R36","doi-asserted-by":"crossref","first-page":"3474","DOI":"10.1073\/pnas.0307402101","article-title":"Hearing loss and retarded cochlear development in mice lacking type 2 iodothyronine deiodinase.","volume":"101","author":"Ng","year":"2004","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071614040389600_R37","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1159\/000076000","article-title":"Hearing loss in athyroid pax8 knockout mice and effects of thyroxine substitution.","volume":"9","author":"Christ","year":"2004","journal-title":"Audiol Neurootol"},{"key":"2020071614040389600_R38","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1038\/nature01059","article-title":"Prestin is required for electromotility of the outer hair cell and for the cochlear amplifier.","volume":"419","author":"Liberman","year":"2002","journal-title":"Nature"},{"key":"2020071614040389600_R39","doi-asserted-by":"crossref","first-page":"39046","DOI":"10.1074\/jbc.M103385200","article-title":"Thyroid hormone-deficient period prior to the onset of hearing is associated with reduced levels of \u03b2-tectorin protein in the tectorial membrane. Implication for hearing loss.","volume":"276","author":"Knipper","year":"2001","journal-title":"J Biol Chem"},{"key":"2020071614040389600_R40","doi-asserted-by":"crossref","first-page":"2901","DOI":"10.1073\/pnas.052609899","article-title":"Thyroid hormone is a critical determinant for the regulation of the cochlear motor protein prestin.","volume":"99","author":"Weber","year":"2002","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071614040389600_R41","doi-asserted-by":"crossref","first-page":"2975","DOI":"10.1242\/jcs.03013","article-title":"Thyroid hormone receptors TR\u03b11 and TR\u03b2 differentially regulate gene expression of Kcnq4 and prestin during final differentiation of outer hair cells.","volume":"119","author":"Winter","year":"2006","journal-title":"J Cell Sci"},{"key":"2020071614040389600_R42","doi-asserted-by":"crossref","first-page":"3624","DOI":"10.1210\/endo.138.9.5412","article-title":"Thyrotropin regulation by thyroid hormone in thyroid hormone receptor \u03b2-deficient mice.","volume":"138","author":"Weiss","year":"1997","journal-title":"Endocrinology"},{"key":"2020071614040389600_R43","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/S0378-5955(99)00003-9","article-title":"Assessment of hearing in 80 inbred strains of mice by ABR threshold analyses.","volume":"130","author":"Zheng","year":"1999","journal-title":"Hear Res"}],"container-title":["Molecular Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/mend\/article-pdf\/21\/7\/1593\/8961160\/mend1593.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/mend\/article-pdf\/21\/7\/1593\/8961160\/mend1593.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,7,16]],"date-time":"2020-07-16T21:19:17Z","timestamp":1594934357000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/mend\/article\/21\/7\/1593\/2738480"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2007,7,1]]},"references-count":43,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2007,7,1]]}},"URL":"https:\/\/doi.org\/10.1210\/me.2007-0085","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.1089393.543645","asserted-by":"object"}]},"ISSN":["0888-8809","1944-9917"],"issn-type":[{"value":"0888-8809","type":"print"},{"value":"1944-9917","type":"electronic"}],"subject":[],"published":{"date-parts":[[2007,7,1]]}}}