{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T20:33:40Z","timestamp":1777149220255,"version":"3.51.4"},"posted":{"date-parts":[[2026,4,22]]},"group-title":"Endocrinology (including Diabetes Mellitus and Metabolic Disease)","reference-count":25,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T00:00:00Z","timestamp":1776816000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>\n                    Heterozygous c.283+1G&gt;A and c.283G&gt;A variants in the\n                    <jats:italic>THRB<\/jats:italic>\n                    gene, encoding for thyroid hormone receptor (TR)\u03b21 and \u03b22, lead to autosomal dominant macular dystrophy (ADMD). We report the detailed clinical characterization of two first-degree relatives with ADMD, heterozygous for\n                    <jats:italic>THRB<\/jats:italic>\n                    c.283+1G&gt;A, and an unrelated ADMD patient with a novel variant, c.283G&gt;C. The genomic and molecular consequences of both variants were studied.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    gDNA and mRNA were obtained from leukocytes. Clinical characterization included biochemistry, bone density and body composition, ECG, echocardiography, ultrasound, audiometry and color-vision.\n                    <jats:italic>In vitro<\/jats:italic>\n                    assays investigated TR function and DNA binding.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    The patients manifested no resistance to thyroid hormone beta (RTH\u03b2) and had normal FT4 and TSH. Detailed studies in two patients showed no goiter, tachycardia, hypercholesterinemia or hepatic steatosis. Hearing was not impaired. Both had impaired color vision and reduced bone density. RT-PCR from all three patients revealed skipping of exon 4 exclusive to TR\u03b21, producing a deletion of 87 amino acids in the N-terminal domain (TR\u03b21\n                    <jats:sup>\u0394NTD<\/jats:sup>\n                    ).\n                    <jats:italic>In vitro<\/jats:italic>\n                    , DNA-binding affinity of TR\u03b21\n                    <jats:sup>\u0394NTD<\/jats:sup>\n                    to DR4-TRE with or without RXR\u03b1 was comparable to TR\u03b21\n                    <jats:sup>WT<\/jats:sup>\n                    . Surprisingly, TR\u03b21\n                    <jats:sup>\u0394NTD<\/jats:sup>\n                    was transcriptionally twice more active than TR\u03b21\n                    <jats:sup>WT<\/jats:sup>\n                    with a similar EC\n                    <jats:sub>50<\/jats:sub>\n                    for T3, demonstrating gain-of-function of TR\u03b21\n                    <jats:sup>\u0394NTD<\/jats:sup>\n                    .\n                    <jats:italic>THRA<\/jats:italic>\n                    expression in leukocytes was increased by 3-fold compared to unrelated controls and different from RTH\u03b2 patients.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>\n                    These\n                    <jats:italic>THRB<\/jats:italic>\n                    splice site variants produce TR\u03b21 exon 4 skipping, resulting in a gain-of-function mutant, TR\u03b21\n                    <jats:sup>\u0394NTD<\/jats:sup>\n                    . This explains the dominant ADMD phenotype devoid of RTH\u03b2 and suggests a TR\u03b21 gain-of-function syndrome.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.04.15.26349265","type":"posted-content","created":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T15:45:19Z","timestamp":1776872719000},"source":"Crossref","is-referenced-by-count":0,"title":["<i>THRB<\/i>\n                  splice site variants lead to exon 4 skipping and TR\u03b21 gain-of-function syndrome"],"prefix":"10.64898","author":[{"given":"Georg Sebastian","family":"H\u00f6nes","sequence":"first","affiliation":[{"name":"Department of Endocrinology, Diabetes and Metabolism and Division of Laboratory Research, Center for Rare Endocrine Diseases\/Endo-ERN, University Hospital Essen, Essen, Germany"},{"name":"Center Endocrine Medicine, University Hospital Essen, Essen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiao-Hui","family":"Liao","sequence":"additional","affiliation":[{"name":"Department of Medicine, The University of Chicago, Chicago, IL USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisa Annabelle","family":"Mahler","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University Hospital Bonn, Bonn, Germany"},{"name":"Ophthalmology Department, Necker Enfants Malades University Hospital, Assistance Publique-H\u00f4pitaux de Paris (AP-HP), Paris Cit\u00e9 University, 75015 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philipp","family":"Herrmann","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University Hospital Bonn, Bonn, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anja","family":"Eckstein","sequence":"additional","affiliation":[{"name":"Center Endocrine Medicine, University Hospital Essen, Essen, Germany"},{"name":"Department of Ophthalmology, Center for Endocrine Medicine, University Hospital Essen, Essen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dagmar","family":"F\u00fchrer","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Diabetes and Metabolism and Division of Laboratory Research, Center for Rare Endocrine Diseases\/Endo-ERN, University Hospital Essen, Essen, Germany"},{"name":"Center Endocrine Medicine, University Hospital Essen, Essen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jesus Moreno","family":"Castillo","sequence":"additional","affiliation":[{"name":"Department of Medicine, The University of Chicago, Chicago, IL USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Chiang","sequence":"additional","affiliation":[{"name":"Molecular Vision Laboratory Hillsboro, Oregon, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea Louise","family":"Vincent","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, New Zealand National Eye Centre, Faculty of Medical and Health Science University of Auckland, Auckland, and Eye Department Greenlane Clinical Centre, Te"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roy E.","family":"Weiss","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA. Toka Tumai, Health New Zealand, Te Whatu Ora, Auckland New Zealand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexandra Mihaela","family":"Dumitrescu","sequence":"additional","affiliation":[{"name":"Department of Medicine, The University of Chicago, Chicago, IL USA"},{"name":"Committee on Molecular Metabolism and Nutrition, The University of Chicago, Chicago, IL USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samuel","family":"Refetoff","sequence":"additional","affiliation":[{"name":"Department of Medicine, The University of Chicago, Chicago, IL USA"},{"name":"Department of Pediatrics and Committee on Genetics, The University of Chicago, Chicago, IL USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9330-9036","authenticated-orcid":false,"given":"Lars Christian","family":"Moeller","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Diabetes and Metabolism and Division of Laboratory Research, Center for Rare Endocrine Diseases\/Endo-ERN, University Hospital Essen, Essen, Germany"},{"name":"Center Endocrine Medicine, University Hospital Essen, Essen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026042512401093000_2026.04.15.26349265v1.1","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2019.0763"},{"key":"2026042512401093000_2026.04.15.26349265v1.2","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2023.1174600"},{"key":"2026042512401093000_2026.04.15.26349265v1.3","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2021.656551"},{"key":"2026042512401093000_2026.04.15.26349265v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagen.2012.08.005"},{"key":"2026042512401093000_2026.04.15.26349265v1.5","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2023.1197744"},{"key":"2026042512401093000_2026.04.15.26349265v1.6","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-025-97768-9"},{"key":"2026042512401093000_2026.04.15.26349265v1.7","doi-asserted-by":"publisher","DOI":"10.3390\/genes16101240"},{"key":"2026042512401093000_2026.04.15.26349265v1.8","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1706801115"},{"key":"2026042512401093000_2026.04.15.26349265v1.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2023.112088"},{"key":"2026042512401093000_2026.04.15.26349265v1.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.12.015"},{"key":"2026042512401093000_2026.04.15.26349265v1.11","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07487-w"},{"key":"2026042512401093000_2026.04.15.26349265v1.12","doi-asserted-by":"publisher","DOI":"10.1210\/jc.78.4.990"},{"key":"2026042512401093000_2026.04.15.26349265v1.13","doi-asserted-by":"publisher","DOI":"10.1089\/105072503770867228"},{"key":"2026042512401093000_2026.04.15.26349265v1.14","doi-asserted-by":"publisher","DOI":"10.1530\/etj-24-0315"},{"key":"2026042512401093000_2026.04.15.26349265v1.15","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1317041111"},{"key":"2026042512401093000_2026.04.15.26349265v1.16","doi-asserted-by":"publisher","DOI":"10.1523\/eneuro.0058-23.2023"},{"key":"2026042512401093000_2026.04.15.26349265v1.17","doi-asserted-by":"publisher","DOI":"10.1186\/s12916-015-0329-0"},{"key":"2026042512401093000_2026.04.15.26349265v1.18","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.16-19735"},{"key":"2026042512401093000_2026.04.15.26349265v1.19","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2016-3671"},{"key":"2026042512401093000_2026.04.15.26349265v1.20","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2020.0651"},{"key":"2026042512401093000_2026.04.15.26349265v1.21","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgab002"},{"key":"2026042512401093000_2026.04.15.26349265v1.22","doi-asserted-by":"publisher","DOI":"10.1038\/nrendo.2013.58"},{"key":"2026042512401093000_2026.04.15.26349265v1.23","doi-asserted-by":"publisher","DOI":"10.1210\/er.2015-1106"},{"key":"2026042512401093000_2026.04.15.26349265v1.24","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.432"},{"key":"2026042512401093000_2026.04.15.26349265v1.25","doi-asserted-by":"publisher","DOI":"10.1021\/acs.accounts.5c00261"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.04.15.26349265","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T19:40:20Z","timestamp":1777146020000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.64898\/2026.04.15.26349265"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,22]]},"references-count":25,"URL":"https:\/\/doi.org\/10.64898\/2026.04.15.26349265","relation":{},"subject":[],"published":{"date-parts":[[2026,4,22]]},"subtype":"preprint"}}