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TSHR
thyroid stimulating hormone receptor
TSHR is located on the long (q) arm of chromosome 14, at band 14q24-q31. Arm ratio per GRCh38 - banding schematic.
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Overview
The TSHR gene encodes the thyroid stimulating hormone receptor, a membrane-spanning protein found on follicular cells within the thyroid gland. This receptor serves as the primary molecular switch controlling thyroid gland development and function, responding to thyroid stimulating hormone signals from the pituitary gland. When activated, the receptor initiates cellular responses that regulate the synthesis and release of thyroid hormones, which are essential for metabolism, growth, and neurological development throughout life.
Variants in TSHR can disrupt normal thyroid function, leading to a spectrum of endocrine disorders. Some changes impair receptor activity, resulting in insufficient thyroid hormone production from birth, whilst others cause the receptor to remain continuously active, driving excessive hormone synthesis. Understanding TSHR function provides insight into how thyroid disorders develop and how they might be managed clinically.
What the gene does
The thyroid stimulating hormone receptor functions as a molecular relay system, transmitting signals from the bloodstream into thyroid follicular cells. The protein spans the cell membrane, with a substantial portion extending outside the cell to capture thyroid stimulating hormone molecules circulating in the blood. When the hormone binds to this external portion, the receptor undergoes structural changes that activate intracellular signalling cascades.
These signalling pathways control multiple aspects of thyroid biology, including the uptake of iodine from the bloodstream, the synthesis of thyroid hormones within follicular cells, and the release of these hormones into circulation. The receptor also influences thyroid gland growth and cellular proliferation, helping to maintain appropriate gland size and structure. By coordinating these diverse functions, the thyroid stimulating hormone receptor ensures that thyroid hormone levels remain within the range needed to support normal metabolic activity across all tissues.
The receptor's activity must be precisely regulated, as both insufficient and excessive signalling can lead to significant health consequences. Normal receptor function depends on proper protein folding, correct positioning in the cell membrane, and the ability to both activate and deactivate in response to hormone binding.
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Chromosome location
TSHR is located on chromosome 14 at the cytogenetic band 14q24-q31, a region on the long arm of chromosome 14. This chromosomal location has been established through genetic mapping studies that positioned the gene within a segment containing other genes involved in endocrine and metabolic regulation. The gene's position at this locus means that large chromosomal deletions or rearrangements affecting this region could potentially disrupt TSHR function alongside neighbouring genes.
Protein structure
The thyroid stimulating hormone receptor protein comprises 764 amino acids organised into distinct functional regions. The extracellular portion contains a series of seven leucine-rich repeat domains (LRR 1 through LRR 7), spanning amino acids 100 through 271. These repeating structural elements form the hormone-binding interface, creating a curved surface that recognises and captures thyroid stimulating hormone with high specificity.
LRR 1 encompasses amino acids 100-124, followed sequentially by LRR 2 (125-150), LRR 3 (152-174), LRR 4 (176-199), LRR 5 (200-223), LRR 6 (227-248), and LRR 7 (250-271). This repetitive architecture is characteristic of the glycoprotein hormone receptor family, providing structural stability and creating the binding pocket for the hormone ligand.
Near the C-terminus, the receptor contains a PDZ-binding motif at amino acids 762-764. This short sequence allows the receptor to interact with scaffolding proteins inside the cell, potentially anchoring it to specific cellular locations and facilitating signal transduction. The arrangement of these domains enables the receptor to perform its dual role of hormone recognition and intracellular signalling activation.
Key variants
Genetic variants in TSHR produce a range of functional consequences depending on their location and effect on protein structure. Some variants prevent the receptor from reaching the cell surface, leaving follicular cells unable to respond to thyroid stimulating hormone signals. Other changes affect the hormone-binding region, reducing the receptor's ability to recognise or respond to the hormone even when properly positioned in the membrane. A distinct class of variants causes constitutive activation, where the receptor signals continuously without requiring hormone binding, leading to uncontrolled thyroid hormone production.
No pathogenic or likely-pathogenic ClinVar variants recorded yet for this gene.
Associated conditions
Variants in TSHR are associated with several thyroid disorders affecting hormone levels and gland function. Congenital hypothyroidism can result from variants that reduce or eliminate receptor function, preventing the thyroid gland from responding to stimulation and leading to insufficient thyroid hormone production from birth. Conversely, activating variants can cause hyperthyroidism, characterised by excessive thyroid hormone synthesis, thyroid gland enlargement, and symptoms including rapid heart rate and metabolic disturbances.
Somatic variants acquired during a person's lifetime have been identified in thyroid tumours, both benign and malignant. These changes are present only in tumour cells and are not inherited. The spectrum of TSHR-associated conditions reflects the receptor's central role in regulating thyroid gland activity and growth.
No disease links recorded for this gene in our reference set.
UK clinical status
Within the NHS Genomic Medicine Service, TSHR appears on multiple clinical gene panels used for diagnostic testing. The gene has been designated green (highest confidence) status on the Congenital Hypothyroidism panel (R145), the DDG2P panel, and the Hyperthyroidism panel (R182). This classification indicates strong evidence supporting the gene's role in these conditions and its inclusion in routine clinical genomic testing pathways for patients presenting with thyroid dysfunction.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does the TSHR gene do?
TSHR encodes a receptor protein on thyroid gland cells that responds to thyroid stimulating hormone from the pituitary gland. When activated, this receptor triggers the production and release of thyroid hormones, which regulate metabolism, growth, and development throughout the body.
How do TSHR variants affect thyroid function?
Variants can either reduce receptor function, leading to insufficient thyroid hormone production and hypothyroidism, or cause the receptor to remain continuously active, resulting in excessive hormone production and hyperthyroidism. The specific effect depends on how the variant changes the protein's structure and activity.
Are TSHR-related conditions treatable?
Many TSHR-related thyroid disorders can be managed with medical treatment. Hypothyroidism is typically treated with thyroid hormone replacement therapy, whilst hyperthyroidism may be managed with medications that reduce hormone production, radioactive iodine therapy, or surgery. Treatment plans are individualised based on the specific condition and clinical presentation.
References
- Park SM, Chatterjee VK. Genetics of congenital hypothyroidism. Journal of medical genetics. 2005. PMID: 15863666