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- Title
Mutations in TBL1X Are Associated With Central Hypothyroidism.
- Authors
Heinen, Charlotte A; Losekoot, Monique; Sun, Yu; Watson, Peter J; Fairall, Louise; Joustra, Sjoerd D; Zwaveling-Soonawala, Nitash; Oostdijk, Wilma; van den Akker, Erica L T; Alders, Mariëlle; Santen, Gijs W E; van Rijn, Rick R; Dreschler, Wouter A; Surovtseva, Olga V; Biermasz, Nienke R; Hennekam, Raoul C; Wit, Jan M; Schwabe, John W R; Boelen, Anita; Fliers, Eric
- Abstract
<bold>Context: </bold>Isolated congenital central hypothyroidism (CeH) can result from mutations in TRHR, TSHB, and IGSF1, but its etiology often remains unexplained. We identified a missense mutation in the transducin β-like protein 1, X-linked (TBL1X) gene in three relatives diagnosed with isolated CeH. TBL1X is part of the thyroid hormone receptor-corepressor complex.<bold>Objective: </bold>The objectives of the study were the identification of TBL1X mutations in patients with unexplained isolated CeH, Sanger sequencing of relatives of affected individuals, and clinical and biochemical characterization; in vitro investigation of functional consequences of mutations; and mRNA expression in, and immunostaining of, human hypothalami and pituitary glands.<bold>Design: </bold>This was an observational study.<bold>Setting: </bold>The study was conducted at university medical centers.<bold>Patients: </bold>Nineteen individuals with and seven without a mutation participated in the study.<bold>Main Outcome Measures: </bold>Outcome measures included sequencing results, clinical and biochemical characteristics of mutation carriers, and results of in vitro functional and expression studies.<bold>Results: </bold>Sanger sequencing yielded five additional mutations. All patients (n = 8; six males) were previously diagnosed with CeH (free T4 [FT4] concentration below the reference interval, normal thyrotropin). Eleven relatives (two males) also carried mutations. One female had CeH, whereas 10 others had low-normal FT4 concentrations. As a group, adult mutation carriers had 20%-25% lower FT4 concentrations than controls. Twelve of 19 evaluated carriers had hearing loss. Mutations are located in the highly conserved WD40-repeat domain of the protein, influencing its expression and thermal stability. TBL1X mRNA and protein are expressed in the human hypothalamus and pituitary.<bold>Conclusions: </bold>TBL1X mutations are associated with CeH and hearing loss. FT4 concentrations in mutation carriers vary from low-normal to values compatible with CeH.
- Subjects
RNA metabolism; GENEALOGY; GENETIC techniques; HEARING disorders; HYPOTHALAMUS; HYPOTHYROIDISM; GENETIC mutation; PITUITARY gland; THYROXINE; GENETIC carriers; DISEASE complications
- Publication
Journal of Clinical Endocrinology & Metabolism, 2016, pjc20162531
- ISSN
0021-972X
- Publication type
journal article