ReviewThe Journal of clinical endocrinology and metabolism2017
Central Hypothyroidism Due to a TRHR Mutation Causing Impaired Ligand Affinity and Transactivation of Gq.
Review in The Journal of clinical endocrinology and metabolism, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers, 1 of them a synthesis that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
15 citing papers in PubMed, 1 synthesis or guideline pooled it, 31 citations in OpenAlex.
- [Clinical guideline of «congenital hypothyroidism»].Problemy endokrinologii · 2022Guideline
- New Insights into Iodide Transport Defects (ITDs) from the Characterization of a Heterozygous NIS Missense Variant (p.G288S) Identified in a Family with Thyroid Dysfunction During Pregnancy.International journal of molecular sciences · 2026Article
- Carrier screening in the reproductive setting-Are there medical implications for the heterozygote?-A guide for clinicians.Pregnancy (Hoboken, N.J.) · 2026Review
- Newborn screening for central congenital hypothyroidism: past, present and future.European thyroid journal · 2025Review
- How Protein Depletion Balances Thrombosis and Bleeding Risk in the Context of Platelet's Activatory and Negative Signaling.International journal of molecular sciences · 2024Review
- Article
- Regulation of Thyroid Hormone Levels by Hypothalamic Thyrotropin-Releasing Hormone Neurons.Thyroid : official journal of the American Thyroid Association · 2023Article
- Genetic Basis of Congenital Central Hypothyroidism in Children: Expanding the Mutational Spectrum of POU1F1 and ATP6V0A4.International journal of general medicine · 2023Article
- Biochemical and physiological insights into TRH receptor-mediated signaling.Frontiers in cell and developmental biology · 2022Review
- Diagnosis and Management of Central Congenital Hypothyroidism.Frontiers in endocrinology · 2021Review
- IGSF1 Deficiency Results in Human and Murine Somatotrope Neurosecretory Hyperfunction.The Journal of clinical endocrinology and metabolism · 2020Article
- A Gq Biased Small Molecule Active at the TSH Receptor.Frontiers in endocrinology · 2020Article
- Recent advances in research on isolated congenital central hypothyroidism.Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology · 2019Article
- Central Hypothyroidism and Novel Clinical Phenotypes in Hemizygous Truncation ofJournal of the Endocrine Society · 2019Article
- 2018 European Thyroid Association (ETA) Guidelines on the Diagnosis and Management of Central Hypothyroidism.European thyroid journal · 2018Article
Corrections and comments
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Authors and funding
6 authors at 4 institutions in 2 countries.
Funding
Abstract
Context: Central congenital hypothyroidism (CCH) is an underdiagnosed disorder characterized by deficient production and bioactivity of thyroid-stimulating hormone (TSH) leading to low thyroid hormone synthesis. Thyrotropin-releasing hormone (TRH) receptor (TRHR) defects are rare recessive disorders usually associated with incidentally identified CCH and short stature in childhood. Objectives: Clinical and genetic characterization of a consanguineous family of Roma origin with central hypothyroidism and identification of underlying molecular mechanisms. Design: All family members were phenotyped with thyroid hormone profiles, pituitary magnetic resonance imaging, TRH tests, and dynamic tests for other pituitary hormones. Candidate TRH, TRHR, TSHB, and IGSF1 genes were screened for mutations. A mutant TRHR was characterized in vitro and by molecular modeling. Results: A homozygous missense mutation in TRHR (c.392T > C; p.I131T) was identified in an 8-year-old boy with moderate hypothyroidism (TSH: 2.61 mIU/L, Normal: 0.27 to 4.2; free thyroxine: 9.52 pmol/L, Normal: 10.9 to 25.7) who was overweight (body mass index: 20.4 kg/m2, p91) but had normal stature (122 cm; -0.58 standard deviation). His mother, two brothers, and grandmother were heterozygous for the mutation with isolated hyperthyrotropinemia (TSH: 4.3 to 8 mIU/L). The I131T mutation, in TRHR intracellular loop 2, decreases TRH affinity and increases the half-maximal effective concentration for signaling. Modeling of TRHR-Gq complexes predicts that the mutation disrupts the interaction between receptor and a hydrophobic pocket formed by Gq. Conclusions: A unique missense TRHR defect identified in a consanguineous family is associated with central hypothyroidism in homozygotes and hyperthyrotropinemia in heterozygotes, suggesting compensatory elevation of TSH with reduced biopotency. The I131T mutation decreases TRH binding and TRHR-Gq coupling and signaling.
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