{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T04:45:09Z","timestamp":1771303509983,"version":"3.50.1"},"reference-count":20,"publisher":"Oxford University Press (OUP)","issue":"5","content-domain":{"domain":["eje.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2012,11]]},"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Individuals carrying a heterozygous inactivating<jats:italic>PAX8<\/jats:italic>mutation are affected by congenital hypothyroidism (CH), although heterozygous<jats:italic>Pax8<\/jats:italic>knockout mice are not. It has remained unclear whether CH in<jats:italic>PAX8<\/jats:italic>mutation carriers is caused by haploinsufficiency or a dominant negative mechanism.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>To report clinical and molecular findings of four novel<jats:italic>PAX8<\/jats:italic>mutations, including one early-truncating frameshift mutation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Subjects and methods<\/jats:title><jats:p>Four probands were CH patients. Two had family history of congenital or childhood hypothyroidism. Three probands were diagnosed in the frame of newborn screening for CH, while one had a negative result in screening but was diagnosed subsequently. Three had thyroid hypoplasia and one had a slightly small thyroid with low echogenicity. For these probands and their family members, we sequenced<jats:italic>PAX8<\/jats:italic>using a standard PCR-based method. Pathogenicity of identified mutations was verified<jats:italic>in vitro<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We found four novel heterozygous<jats:italic>PAX8<\/jats:italic>mutations in the four probands: L16P, F20S, D46SfsX24, and R133Q. Family studies showed four additional mutation carriers, who were confirmed to have high serum TSH levels. Expression experiments revealed that three mutations (L16P, F20S, and R133Q) had defects in target DNA binding, while D46fs had protein instability that was rescued by the proteasome inhibitor MG132. All four mutations had reduced transactivation on the thyroglobulin promoter, supporting that they were inactivating mutations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>D46fs is the first<jats:italic>PAX8<\/jats:italic>mutation with confirmed protein instability. Our clinical and<jats:italic>in vitro<\/jats:italic>findings together suggest that pure<jats:italic>PAX8<\/jats:italic>haploinsufficiency can cause CH in humans.<\/jats:p><\/jats:sec>","DOI":"10.1530\/eje-12-0410","type":"journal-article","created":{"date-parts":[[2012,8,17]],"date-time":"2012-08-17T03:24:14Z","timestamp":1345173854000},"page":"625-632","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-1","source":"Crossref","is-referenced-by-count":27,"title":["Functional characterization of four novel PAX8 mutations causing congenital hypothyroidism: new evidence for haploinsufficiency as a disease mechanism"],"prefix":"10.1093","volume":"167","author":[{"given":"Satoshi","family":"Narumi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shunsuke","family":"Araki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naoaki","family":"Hori","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Koji","family":"Muroya","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yukiyo","family":"Yamamoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yumi","family":"Asakura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masanori","family":"Adachi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomonobu","family":"Hasegawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","reference":[{"issue":"2","key":"1_9359108","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1242\/dev.110.2.643","volume":"110","author":"Plachov","year":"1990","journal-title":"Development","ISSN":"https:\/\/id.crossref.org\/issn\/0950-1991","issn-type":"print"},{"issue":"9","key":"2_9942145","doi-asserted-by":"crossref","first-page":"4230","DOI":"10.1128\/MCB.12.9.4230","volume":"12","author":"Zannini","year":"1992","journal-title":"Molecular and Cellular Biology","ISSN":"https:\/\/id.crossref.org\/issn\/0270-7306","issn-type":"print"},{"issue":"1","key":"3_6002776","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1038\/1757","volume":"19","author":"Mansouri","year":"1998","journal-title":"Nature genetics","ISSN":"https:\/\/id.crossref.org\/issn\/1061-4036","issn-type":"print"},{"issue":"8","key":"4_11277706","doi-asserted-by":"publisher","first-page":"3962","DOI":"10.1210\/jc.86.8.3962","volume":"86","author":"Congdon","year":"2001","journal-title":"Journal of Clinical Endocrinology &amp; 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