The Journal of clinical endocrinology and metabolism · 2016
Mutations in TBL1X Are Associated With Central Hypothyroidism.
СтатьяНаблюдательное исследованиеПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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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
Аннотация
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.
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.