{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,17]],"date-time":"2026-05-17T04:39:26Z","timestamp":1778992766236,"version":"3.51.4"},"reference-count":38,"publisher":"The Endocrine Society","issue":"2","license":[{"start":{"date-parts":[[2020,11,3]],"date-time":"2020-11-03T00:00:00Z","timestamp":1604361600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001826","name":"Netherlands Organisation for Health Research and Development","doi-asserted-by":"publisher","award":["113303005"],"award-info":[{"award-number":["113303005"]}],"id":[{"id":"10.13039\/501100001826","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Sherman Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,1,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Context<\/jats:title>\n                  <jats:p>Genetic variants in SLC16A2, encoding the thyroid hormone transporter MCT8, can cause intellectual and motor disability and abnormal serum thyroid function tests, known as MCT8 deficiency. The C-terminal domain of MCT8 is poorly conserved, which complicates prediction of the deleteriousness of variants in this region. We studied the functional consequences of 5 novel variants within this domain and their relation to the clinical phenotypes.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We enrolled male subjects with intellectual disability in whom genetic variants were identified in exon 6 of SLC16A2. The impact of identified variants was evaluated in transiently transfected cell lines and patient-derived fibroblasts.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Seven individuals from 5 families harbored potentially deleterious variants affecting the C-terminal domain of MCT8. Two boys with clinical features considered atypical for MCT8 deficiency had a missense variant [c.1724A&amp;gt;G;p.(His575Arg) or c.1796A&amp;gt;G;p.(Asn599Ser)] that did not affect MCT8 function in transfected cells or patient-derived fibroblasts, challenging a causal relationship. Two brothers with classical MCT8 deficiency had a truncating c.1695delT;p.(Val566*) variant that completely inactivated MCT8 in vitro. The 3 other boys had relatively less-severe clinical features and harbored frameshift variants that elongate the MCT8 protein [c.1805delT;p.(Leu602HisfsTer680) and c.del1826-1835;p.(Pro609GlnfsTer676)] and retained ~50% residual activity. Additional truncating variants within transmembrane domain 12 were fully inactivating, whereas those within the intracellular C-terminal tail were tolerated.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Variants affecting the intracellular C-terminal tail of MCT8 are likely benign unless they cause frameshifts that elongate the MCT8 protein. These findings provide clinical guidance in the assessment of the pathogenicity of variants within the C-terminal domain of MCT8.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1210\/clinem\/dgaa795","type":"journal-article","created":{"date-parts":[[2020,11,3]],"date-time":"2020-11-03T13:41:15Z","timestamp":1604410875000},"page":"539-553","source":"Crossref","is-referenced-by-count":8,"title":["Clinical and Functional Consequences of C-Terminal Variants in MCT8: A Case Series"],"prefix":"10.1210","volume":"106","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6960-5775","authenticated-orcid":false,"given":"Ferdy S","family":"van Geest","sequence":"first","affiliation":[{"name":"Academic Center For Thyroid Disease, Department of Internal Medicine, Erasmus Medical Center, GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcel E","family":"Meima","sequence":"additional","affiliation":[{"name":"Academic Center For Thyroid Disease, Department of Internal Medicine, Erasmus Medical Center, GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kyra E","family":"Stuurman","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Erasmus Medical Center, GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1721-0728","authenticated-orcid":false,"given":"Nicole I","family":"Wolf","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology, Emma Children\u2019s Hospital, Amsterdam University Medical Centre, AZ Amsterdam, Netherlands"},{"name":"Amsterdam Neuroscience, HV Amsterdam, Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marjo S","family":"van der Knaap","sequence":"additional","affiliation":[{"name":"Department of Pediatric Neurology, Emma Children\u2019s Hospital, Amsterdam University Medical Centre, AZ Amsterdam, Netherlands"},{"name":"Amsterdam Neuroscience, HV Amsterdam, Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cl\u00e1udia F","family":"Lorea","sequence":"additional","affiliation":[{"name":"Teaching Hospital of Universidade Federal de Pelotas, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fabiano O","family":"Poswar","sequence":"additional","affiliation":[{"name":"Medical Genetics Service, Hospital de Cl\u00ednicas de Porto Alegre, Porto Alegre, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Filippo","family":"Vairo","sequence":"additional","affiliation":[{"name":"Department of Clinical Genomics, Mayo Clinic, Rochester, Minnesota, USA"},{"name":"Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, 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Munnik","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Radboud University Medical Centre Nijmegen, GA Nijmegen, the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7732-9371","authenticated-orcid":false,"given":"Robin P","family":"Peeters","sequence":"additional","affiliation":[{"name":"Academic Center For Thyroid Disease, Department of Internal Medicine, Erasmus Medical Center, GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"W Edward","family":"Visser","sequence":"additional","affiliation":[{"name":"Academic Center For Thyroid Disease, Department of Internal Medicine, Erasmus Medical Center, GD Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefan","family":"Groeneweg","sequence":"additional","affiliation":[{"name":"Academic Center For Thyroid Disease, Department of Internal Medicine, Erasmus Medical 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