Details

Autor(en) / Beteiligte

• 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
• van Trotsenburg, A. S. Paul

Titel

Mutations in TBL1X Are Associated With Central Hypothyroidism

Ist Teil von

• The journal of clinical endocrinology and metabolism, 2016-12, Vol.101 (12), p.4564-4573

Ort / Verlag

United States: Endocrine Society

Erscheinungsjahr

2016

Quelle

Oxford Journals 2020 Medicine

Beschreibungen/Notizen

• Context: 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. Objective: 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. 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 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. Conclusions: TBL1X mutations are associated with CeH and hearing loss. FT4 concentrations in mutation carriers vary from low-normal to values compatible with CeH. By using DNA-analysis, clinical and biochemical phenotyping, and in vitro functional and expression studies, we show that TBL1X mutations are associated with central hypothyroidism and hearing loss.