Mutations in TBL1X Are Associated With Central Hypothyroidism

作者：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, Marielle; 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^*; van Trotsenburg, A. S. Paul

来源：Journal of Clinical Endocrinology & Metabolism, 2016, 101(12): 4564-4573.

DOI：10.1210/jc.2016-2531

• BINDING PROTEIN
• GENE
• DEFICIENCY
• SUBUNIT
• COMPLEX
• HDAC3
• SIZE

Context: Isolated congenital central hypothyroidism (CeH) can result from mutations in TRHR, TSHB, and IGSFI, but its etiology often remains unexplained. We identified a missense mutation in the transducin Ii-like protein 1, X-linked (TBLIX) gene in three relatives diagnosed with isolated CeH. TBL1X is part of the thyroid hormone receptor-corepressor complex. @@@ Objective: The objectives of the study were the identification of TBLIX 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. @@@ Design: This was an observational study. @@@ Setting: The study was conducted at university medical centers. @@@ Patients: Nineteen individuals with and seven without a mutation participated in the study. @@@ Main Outcome Measures: Outcome measures included sequencing results, clinical and biochemical characteristics of mutation carriers, and results of in vitro functional and expression studies. @@@ Results: 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 thyrotropi n). 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. @@@ Conclusions: TBLIX mutations are associated with CeH and hearing loss. FT4 concentrations in mutation carriers vary from low-normal to values compatible with CeH.

• 出版日期2016-12
• 单位上海交通大学