Mutations in TBL1X Are Associated With Central Hypothyroidism

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 ␤-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 ϭ 8; six males) were previously diagnosed with CeH (free T 4 [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. C entral hypothyroidism (CeH) is characterized by suboptimal thyroid hormone (TH) secretion due to insufficient stimulation by TSH of an otherwise normal thyroid gland. CeH may be caused by congenital or acquired disorders of the pituitary gland or hypothalamus (1). The diagnosis is based on a plasma free T 4 (FT4) concentration below the reference interval in combination with an inappropriately normal TSH. Congenital CeH has an esti- Conclusion