The TSHR gene provides instructions for making a protein, known as a receptor, that attaches (binds) to a hormone called thyroid stimulating hormone (TSH). This receptor spans the membrane of certain cells (called follicular cells) in the thyroid gland, a butterfly-shaped tissue in the lower neck. A large part of the receptor sits on the outer surface of the cell (extracellular), and a small portion is retained inside the cell (intracellular). Thyroid stimulating hormone binds to the extracellular portion of the receptor like a key fitting into a lock, activating a series of reactions that control development of the thyroid gland and its functions. Among its functions, the thyroid gland produces iodine-containing hormones (thyroid hormones), which help regulate growth, brain development, and the rate of chemical reactions in the body (metabolism).
Health Conditions Related to Genetic Changes
Several TSHR gene mutations have been identified in people with congenital hypothyroidism, a condition characterized by abnormally low levels of thyroid hormones starting from birth. TSHR gene mutations change one of the protein building blocks (amino acids) used to make the thyroid stimulating hormone receptor. Some of these mutations prevent the receptor from properly spanning the membrane, and in some cases the entire receptor is retained inside the cell. As a result, the receptor cannot interact properly with thyroid stimulating hormone. Other mutations impair the receptor's ability to bind with thyroid stimulating hormone, even though the receptor correctly spans the membrane.
Without properly functioning receptors, thyroid hormone production is not stimulated. The body tries to correct the blocked stimulation by producing more thyroid stimulating hormone. In some cases, the increased levels of thyroid stimulating hormone compensate for receptors with minor defects, and the thyroid functions normally. In other cases, thyroid hormone levels remain low, causing mild to severe congenital hypothyroidism. Impaired thyroid stimulating hormone receptors may also disrupt thyroid development, and as a result, the gland is smaller than normal. Cases of congenital hypothyroidism caused by TSHR gene mutations are sometimes classified as thyroid dysgenesis because development of the thyroid gland is impaired.More About This Health Condition
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TSHR gene mutations can cause disorders associated with hyperthyroidism. These mutations change one of the amino acids used to make the thyroid stimulating hormone receptor. As a result, the receptor is continuously activated and overstimulates the production of thyroid hormones. TSHR gene mutations can lead to an enlarged thyroid gland (goiter) and symptoms of hyperthyroidism, such as a rapid heartbeat. Hyperthyroidism that is present from birth is called nonautoimmune congenital hyperthyroidism (or sporadic toxic thyroid hyperplasia). Onset of hyperthyroidism that begins in childhood or adulthood is known as nonautoimmune autosomal dominant hyperthyroidism (or hereditary toxic thyroid hyperplasia).
Sometimes gene mutations are acquired during a person's lifetime and are present only in certain cells. This type of mutation is called somatic, and it is not inherited. Somatic mutations in the TSHR gene have been identified in thyroid tumors. These mutations are found only in the tumor cells.
Somatic TSHR gene mutations have been reported in many cases of noncancerous (benign) thyroid tumors, called nodules or adenomas, which are associated with an overactive thyroid (hyperthyroidism). Somatic mutations have also been identified in some cancerous (malignant) thyroid tumors known as thyroid carcinomas. As a result of these somatic mutations, the thyroid stimulating hormone receptor is continuously activated, which could prompt the overgrowth of thyroid cells.
Other Names for This Gene
- thyrotropin receptor
- TSH Receptors
Additional Information & Resources
Tests Listed in the Genetic Testing Registry
Scientific Articles on PubMed
- Abramowicz MJ, Duprez L, Parma J, Vassart G, Heinrichs C. Familial congenital hypothyroidism due to inactivating mutation of the thyrotropin receptor causing profound hypoplasia of the thyroid gland. J Clin Invest. 1997 Jun 15;99(12):3018-24. doi: 10.1172/JCI119497. Citation on PubMed or Free article on PubMed Central
- Bas VN, Cangul H, Agladioglu SY, Kendall M, Cetinkaya S, Maher ER, Aycan Z. Mild and severe congenital primary hypothyroidism in two patients by thyrotropin receptor (TSHR) gene mutation. J Pediatr Endocrinol Metab. 2012;25(11-12):1153-6. doi: 10.1515/jpem-2012-0211. Citation on PubMed
- Biebermann H, Schoneberg T, Krude H, Schultz G, Gudermann T, Gruters A. Mutations of the human thyrotropin receptor gene causing thyroid hypoplasia and persistent congenital hypothyroidism. J Clin Endocrinol Metab. 1997 Oct;82(10):3471-80. doi: 10.1210/jcem.82.10.4286. Citation on PubMed
- Cangul H, Aycan Z, Saglam H, Forman JR, Cetinkaya S, Tarim O, Bober E, Cesur Y, Kurtoglu S, Darendeliler F, Bas V, Eren E, Demir K, Kiraz A, Aydin BK, Karthikeyan A, Kendall M, Boelaert K, Shaw NJ, Kirk J, Hogler W, Barrett TG, Maher ER. TSHR is the main causative locus in autosomal recessively inherited thyroid dysgenesis. J Pediatr Endocrinol Metab. 2012;25(5-6):419-26. doi: 10.1515/jpem-2012-0053. Citation on PubMed
- Cangul H, Saglam H, Saglam Y, Eren E, Dogan D, Kendall M, Tarim O, Maher ER, Barrett TG. An essential splice site mutation (c.317+1G>A) in the TSHR gene leads to severe thyroid dysgenesis. J Pediatr Endocrinol Metab. 2014 Sep;27(9-10):1021-5. doi: 10.1515/jpem-2014-0048. Citation on PubMed
- Castro I, Lima L, Seoane R, Lado-Abeal J. Identification and functional characterization of two novel activating thyrotropin receptor mutants in toxic thyroid follicular adenomas. Thyroid. 2009 Jun;19(6):645-9. doi: 10.1089/thy.2009.0002. Citation on PubMed
- Davies TF, Ando T, Lin RY, Tomer Y, Latif R. Thyrotropin receptor-associated diseases: from adenomata to Graves disease. J Clin Invest. 2005 Aug;115(8):1972-83. doi: 10.1172/JCI26031. Citation on PubMed or Free article on PubMed Central
- Gozu H, Avsar M, Bircan R, Sahin S, Ahiskanali R, Gulluoglu B, Deyneli O, Ones T, Narin Y, Akalin S, Cirakoglu B. Does a Leu 512 Arg thyrotropin receptor mutation cause an autonomously functioning papillary carcinoma? Thyroid. 2004 Nov;14(11):975-80. doi: 10.1089/thy.2004.14.975. Citation on PubMed
- Park SM, Chatterjee VK. Genetics of congenital hypothyroidism. J Med Genet. 2005 May;42(5):379-89. doi: 10.1136/jmg.2004.024158. Citation on PubMed or Free article on PubMed Central
- Refetoff S. Resistance to thyrotropin. J Endocrinol Invest. 2003 Aug;26(8):770-9. doi: 10.1007/BF03347364. Citation on PubMed
- Russo D, Costante G, Bruno R, Sponziello M, Tamburrano G, Dima M, Sacco R, Giacomelli L, Durante C, Filetti S. TSH receptor extracellular region mutations in thyroid functioning nodules: further evidence for the functional role of this region in the receptor activation. Endocrine. 2011 Dec;40(3):492-4. doi: 10.1007/s12020-011-9525-7. Epub 2011 Aug 24. No abstract available. Citation on PubMed