TY - JOUR
T1 - Mutations in TBL1X are associated with central hypothyroidism
AU - Heinen, Charlotte A.
AU - Losekoot, Monique
AU - Sun, Yu
AU - Watson, Peter J.
AU - Fairall, Louise
AU - Joustra, Sjoerd D.
AU - Zwaveling-Soonawala, Nitash
AU - Oostdijk, Wilma
AU - Van Den Akker, Erica L.T.
AU - Alders, Mariëlle
AU - Santen, Gijs W.E.
AU - Van Rijn, Rick R.
AU - Dreschler, Wouter A.
AU - Surovtseva, Olga V.
AU - Biermasz, Nienke R.
AU - Hennekam, Raoul C.
AU - Wit, Jan M.
AU - Schwabe, John W.R.
AU - Boelen, Anita
AU - Fliers, Eric
AU - Van Trotsenburg, A. S.Paul
N1 - Publisher Copyright:
© 2016 by the Endocrine Society.
PY - 2016/12
Y1 - 2016/12
N2 - 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 X-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.
AB - 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 X-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.
UR - http://www.scopus.com/inward/record.url?scp=85003587617&partnerID=8YFLogxK
U2 - 10.1210/jc.2016-2531
DO - 10.1210/jc.2016-2531
M3 - Article
C2 - 27603907
AN - SCOPUS:85003587617
SN - 0021-972X
VL - 101
SP - 4564
EP - 4573
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 12
ER -