Mutations in TBL1X Are Associated With Central Hypothyroidism
Open accessAbstract
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: [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.
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Impaired thyrotrope stimulation or alterations in the thyroid hormone feedback set point (e.g., TRH resistance or TBL1X mutations) is a pathological mechanism accounting for central hypothyroidism.
“The pathological mechanisms accounting for CeH are: (a) impaired thyrotrope stimulation or alterations in the thyroid hormone feedback set point (e.g., TRH resistance or TBL1X mutations) [11-13];”
From 2018 European Thyroid Association (ETA) Guidelines on the Diagnosis and Management of Central Hypothyroidism (2018) · cites this paper as [13]
The Abstract concludes that TBL1X mutations are associated with central hypothyroidism. The Discussion proposes that the mutations may disrupt thyroid-hormone-regulated transcription and reduce TRH and TSHB expression, but it does not establish an altered feedback set point as the mechanism. No page numbers are available in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredMutations in TBL1X are a second cause of X-linked central hypothyroidism.
“Mutations in TBL1X are a second cause of X-linked cause of CeH.”
From 2018 European Thyroid Association (ETA) Guidelines on the Diagnosis and Management of Central Hypothyroidism (2018) · cites this paper as [13]
The Abstract (Context and Results; page unavailable) identifies TBL1X as an X-linked gene and reports mutations in patients with central hypothyroidism; the References identify IGSF1 as an earlier X-linked cause. However, the Discussion concludes that TBL1X mutations are associated with central hypothyroidism, rather than establishing them unequivocally as a second cause. (LLM, conf=0.82)
Experimental — accuracy not yet measuredCarriers of TBL1X or IRS4 variants are reported to have lower plasma free thyroxine concentrations, and it remains unclear whether this represents disease or reflects an altered individual set point.
“This is because carriers are reported to have lower plasma FT4 concentrations, and it remains unclear whether this represents disease or reflects an altered individual “set point” (16).”
From Cognitive and Motor Outcome in Patients with Early-Detected Central Congenital Hypothyroidism Compared with Siblings (2021) · cites this paper as [16]
The Results report lower plasma FT4 concentrations in adults with TBL1X mutations than in controls. The Discussion questions whether the lower concentrations cause hypothyroidism in target tissues and considers individual FT4 set points. These passages support the claim for TBL1X carriers, but not its extension to IRS4 carriers; no page numbers were available in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredIn addition to central hypothyroidism, many patients with TBL1X mutations exhibit hearing loss.
“In addition to CeH, many patients exhibit hearing loss [13].”
From 2018 European Thyroid Association (ETA) Guidelines on the Diagnosis and Management of Central Hypothyroidism (2018) · cites this paper as [13]
Isolated central congenital hypothyroidism is associated with X-linked genes.
“A male predominance was seen among patients; this was not unexpected since isolated central CH is associated with X-linked genes (16, 22).”
From Cognitive and Motor Outcome in Patients with Early-Detected Central Congenital Hypothyroidism Compared with Siblings (2021) · cites this paper as [16]
Mutations in IRS4 are another cause of X-linked mild central CH.
“Finally, mutations in IRS4 are another cause of X-linked mild central CH.”
The cause of central CH in IRS4 mutations may be disrupted leptin signaling.
“Since IRS4 is involved in leptin signaling, the cause of the central CH may be disrupted leptin signaling (237).”
Many patients with TBL1X mutations exhibit hearing loss.
“In addition to central CH, many patients exhibit hearing loss (236).”
IRS4 is involved in leptin signaling.
“Since IRS4 is involved in leptin signaling, the cause of the central CH may be disrupted leptin signaling (237).”
Mutations in TBL1X are the second most frequent cause of X-linked central CH.
“Mutations in the TBL1X gene are the second most frequent cause of X-linked central CH.”
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Congenital isolated central hypothyroidism: Novel mutations and their functional implications
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Newborn screening for central congenital hypothyroidism: past, present and future
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Génétique de l’hypothyroïdie congénitale
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Further Delineation of Central Congenital Hypothyroidism due to Variants in TBL1X and IRS4
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- Authors
- Heinen, C. A., Losekoot, M., Sun, Y., Watson, P. J., Fairall, L., Joustra, S. D., Zwaveling-Soonawala, N., Oostdijk, W., van den Akker, E. L. T., Alders, M., Santen, G. W. E., van Rijn, R. R., Dreschler, W. A., Surovtseva, O. V., Biermasz, N. R., Hennekam, R. C., Wit, J. M., Schwabe, J. W. R., Boelen, A., Fliers, E., & van Trotsenburg, A. S. P.
- Affiliations
- University of Leicester (GB)
- Corresponding author
- Fliers, Eric
- ORCID
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2016-12
- Volume
- 101
- Issue
- 12
- Pages
- 4564-4573
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- PMC
- PMC5155687
- OpenAlex
- W2517874194
- Cited by
- 92
- References
- 38
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 10 · 2023: 11 · 2022: 7 · 2021: 8 · 2020: 4 · 2019: 12 · 2018: 16 · 2017: 14 · 2016: 1 · 2015: 1
- FWCI
- 14.41
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
- Pure Amsterdam UMC (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- Leiden Repository (Leiden University) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Leicester Research Archive (University of Leicester) (submittedVersion, cc-by)
- RePub (Erasmus University Rotterdam) (submittedVersion)
- Funders
- Wellcome Trust (100237/Z/12/Z, WT100237)
- Universiteit van Amsterdam
- Directorate for Biological Sciences
- Biotechnology and Biological Sciences Research Council (BB/J009598/1, BB/N002954/1)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
- Keywords
- central hypothyroidism, missense mutations, WD40 repeat domain, mutation carriers, free thyroxine, hearing loss, hypothalamus, pituitary gland, thyroid hormone signaling
- MeSH terms
- Adolescent, Adult, Child, Female, Heterozygote, Humans, Hypothalamus, Hypothyroidism, Infant, Male, Middle Aged, Mutation, Pedigree, Pituitary Gland, RNA, Messenger, Thyroxine, Transducin, Hearing Loss, Young Adult
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