Mutations in TBL1X Are Associated With Central Hypothyroidism.

Charlotte A Heinen ,Monique Losekoot,Olga V Surovtseva,Eric Fliers,John W R Schwabe,Peter J Watson,Anita Boelen,Wouter A Dreschler,Mariëlle Alders,Wilma Oostdijk,Rick R Van Rijn,Nienke R Biermasz,Louise Fairall,Jan M Wit,Nitash Zwaveling-Soonawala,Yu Sun,Gijs W.e Santen ,Erica L T Van Den Akker ,Sjoerd D Joustra ,Raoul C M Hennekam ,A S Paul Van Trotsenburg

doi:10.1210/jc.2016-2531

Abstract

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.

Highlights

MethodsAcquisition of patients In ongoing studies on X-linked central hypothyroidism (CeH), we performed X-exome sequencing in three patients with CeH and two relatives from one family (family A, Figure 1A)
Context: Isolated congenital central hypothyroidism (CeH) can result from mutations in TRHR, TSHB, and IGSF1, but its etiology often remains unexplained
Adult mutation carriers had 20%–25% lower free T4 (FT4) concentrations than controls

Summary

Methods

Acquisition of patients In ongoing studies on X-linked CeH, we performed X-exome sequencing in three patients with CeH and two relatives from one family (family A, Figure 1A). The 25-year-old proband (A.III.8) and his sister’s 1.5-year-old son (A.IV.1) were diagnosed with CeH after detection by the Dutch T4-based neonatal congenital hypothyroidism (CH) screening [2]. They were treated with levothyroxine (LT4) from the ages of 6 months and 16 days, respectively. After identification of a potentially pathogenic TBL1X variant in these patients, Sanger sequencing was performed on DNA samples from 50 unrelated patients with idiopathic CeH, resulting in the discovery of five other mutations in five patients.

Results

Discussion

Conclusion