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Mutations in TBL1X Are Associated With Central Hypothyroidism.

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 ?-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.

SUBMITTER: Heinen CA

PROVIDER: S-EPMC5155687 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Mutations in TBL1X Are Associated With Central Hypothyroidism.

Heinen Charlotte A CA Losekoot Monique M Sun Yu Y Watson Peter J PJ Fairall Louise L Joustra Sjoerd D SD Zwaveling-Soonawala Nitash N Oostdijk Wilma W van den Akker Erica L T EL Alders Mariëlle M Santen Gijs W E GW van Rijn Rick R RR Dreschler Wouter A WA Surovtseva Olga V OV Biermasz Nienke R NR Hennekam Raoul C RC Wit Jan M JM Schwabe John W R JW Boelen Anita A Fliers Eric E van Trotsenburg A S Paul AS

The Journal of clinical endocrinology and metabolism 20160907 12

<h4>Context</h4>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.<h4>Objective</h4>The objectives of the study were the identification of TBL1X mutations in patients with unexplained isolated CeH, S ...[more]

PMID: 27603907

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Project description:BackgroundCentral hypothyroidism (CeH) is a rare condition affecting approximately 1:16 000- 100 000 individuals. Congenital forms can harm normal development if not detected and treated promptly. Clinical and biochemical diagnosis, especially of isolated CeH, can be challenging. Cases are not usually detected in neonatal screening, which, in most countries, is focused on detection of the more prevalent primary hypothyroidism. Until now, five genetic causes for isolated CeH have been identified. Here we aimed to identify the genetic cause in two brothers with impaired growth diagnosed with CeH at the age of 5 years. We further evaluated the candidate gene variants in a large genetic database.MethodsClinical and biochemical characterization together with targeted next-generation sequencing (NGS) was used to identify the genetic cause in a family of two brothers presenting with CeH. Screening of insulin receptor substrate 4 (IRS4) variants was carried out in the FinnGen database.ResultsA novel monoallelic frameshift mutation c.1712_1713insT, p.Gly572Trp fs*32 in the X-linked IRS4 gene was identified by NGS analysis in both affected males and confirmed using Sanger sequencing. Their mother was an unaffected carrier. In addition to the declined growth at presentation, central hypothyroidism and blunted TRH test, no other phenotypic alterations were found. Diagnostic tests included head MRI, thyroid imaging, bone age, and laboratory tests for thyroid autoantibodies, glucose, insulin and glycosylated hemoglobin levels. Examination of the IRS4 locus in FinnGen (R5) database revealed the strongest associations to a rare Finnish haplotype associated with thyroid disorders (p = 1.3e-7) and hypothyroidism (p = 8.3e-7).ConclusionsHere, we identified a novel frameshift mutation in an X-linked IRS4 gene in two brothers with isolated CeH. Furthermore, we demonstrate an association of IRS4 gene locus to a general thyroid disease risk in the FinnGen database. Our findings confirm the role of IRS4 in isolated central hypothyroidism.

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Mutations in TBL1X Are Associated With Central Hypothyroidism.

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Mutations in TBL1X Are Associated With Central Hypothyroidism.

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