ArticleThe Journal of clinical investigation2019
Type 2 deiodinase polymorphism causes ER stress and hypothyroidism in the brain.
Article in The Journal of clinical investigation, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT06083636 (Improvement of Laboratory Diagnostics in Hypothyroid Patients Using Levothyroxine), which is not on this map. Cited by 71 papers, 3 of them syntheses 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.
Improvement of Laboratory Diagnostics in Hypothyroid Patients Using Levothyroxine
Who cites it
71 citing papers in PubMed, 3 syntheses or guidelines pooled it, 112 citations in OpenAlex.
- Selenium Supplementation in Patients with Hashimoto Thyroiditis: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.Thyroid : official journal of the American Thyroid Association · 2024Pooled it
- Evidence-Based Use of Levothyroxine/Liothyronine Combinations in Treating Hypothyroidism: A Consensus Document.Thyroid : official journal of the American Thyroid Association · 2021Guideline
- The Type 2 Deiodinase Thr92Ala Polymorphism Is Associated with Higher Body Mass Index and Fasting Glucose Levels: A Systematic Review and Meta-Analysis.BioMed research international · 2021Pooled it
- Post-Levothyroxine Thyroid Dysfunction in Saudi Arabian Patients with Hypothyroidism: A Cross-Sectional Study.Clinics and practice · 2026Article
- Genetics of selenoproteins and selenoprotein metabolism - An overview of current concepts and emerging aspects.Redox biology · 2026Review
- Thyroid hormones and metabolic flexibility: tissue-specific control of energy homeostasis.Frontiers in physiology · 2026Review
- Novel Phosphatase SSU72 Drives Malignant Progression in Colorectal Cancer via PERKInternational journal of biological sciences · 2026Article
- The type 2 deiodinase Thr92Ala polymorphism and cognitive aging: current evidence and biological context.Therapeutic advances in endocrinology and metabolism · 2026Review
- Endoplasmic reticulum stress in Hashimoto's thyroiditis: a candidate amplification node linking thyroid-specific vulnerability and immune dysregulation.Frontiers in immunology · 2026Review
- Endoplasmic reticulum stress at the forefront of fatty liver diseases and cancer.Pharmacological reviews · 2025Review
- FVB But Not B6 Mice Carrying the Thr92Ala-Dio2 Polymorphism Have Impaired Thyroid Hormonogenesis and Goiter.Endocrinology · 2025Article
- Thyroid Hormone Pathways in Respiratory Diseases: Mechanism and Therapeutic Potential.Journal of inflammation research · 2025Article
- ER stress in D1-MSNs mediates cocaine-induced behavioral plasticityFrontiers in pharmacology · 2025Article
- Metabolic Consequences of Thyroidectomy and Patient-Centered Management.Journal of clinical medicine · 2024Review
- Thr92Ala-DIO2 heterozygosity is associated with skeletal muscle mass and myosteatosis in patients with COVID-19.European thyroid journal · 2024Article
- Mapping Thyroid Hormone Action in the Human Brain.Thyroid : official journal of the American Thyroid Association · 2024Review
- A DIO2 missense mutation and its impact on fetal response to PRRSV infection.BMC veterinary research · 2024Article
- Genetic Background Strongly Influences the Impact of Carrying the Thr92Ala-DIO2 Polymorphism in the Male Mouse.Endocrinology · 2024Article
- Gene polymorphisms and thyroid hormone signaling: implication for the treatment of hypothyroidism.Endocrine · 2024Review
- Brain hypothyroidism silences the immune response of microglia in Alzheimer's disease animal model.Science advances · 2024Article
11 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
22 authors at 6 institutions in 4 countries.
Funding
Abstract
Levothyroxine (LT4) is a form of thyroid hormone used to treat hypothyroidism. In the brain, T4 is converted to the active form T3 by type 2 deiodinase (D2). Thus, it is intriguing that carriers of the Thr92Ala polymorphism in the D2 gene (DIO2) exhibit clinical improvement when liothyronine (LT3) is added to LT4 therapy. Here, we report that D2 is a cargo protein in ER Golgi intermediary compartment (ERGIC) vesicles, recycling between ER and Golgi. The Thr92-to-Ala substitution (Ala92-D2) caused ER stress and activated the unfolded protein response (UPR). Ala92-D2 accumulated in the trans-Golgi and generated less T3, which was restored by eliminating ER stress with the chemical chaperone 4-phenyl butyric acid (4-PBA). An Ala92-Dio2 polymorphism-carrying mouse exhibited UPR and hypothyroidism in distinct brain areas. The mouse refrained from physical activity, slept more, and required additional time to memorize objects. Enhancing T3 signaling in the brain with LT3 improved cognition, whereas restoring proteostasis with 4-PBA eliminated the Ala92-Dio2 phenotype. In contrast, primary hypothyroidism intensified the Ala92-Dio2 phenotype, with only partial response to LT4 therapy. Disruption of cellular proteostasis and reduced Ala92-D2 activity may explain the failure of LT4 therapy in carriers of Thr92Ala-DIO2.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.