TSHR

TSHRs are proteins in the membrane of thyroid cells which bind Thyroid Stimulating Hormone, and regulate thyroid development and production of thyroid hormones.  (Thyroid hormones are very important in the control of growth, brain development, and cellular metabolism.) [R].  

SNP in this gene have been linked to Graves’ disease, an autoimmune disorder that affects production of thyroid hormones.

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).

Background Information:

Rs12101255 refers to a single nucleotide polymorphism (SNP) within the thyroid-stimulating hormone receptor (TSHR) gene [R].

The TSHR gene codes for the receptor that receives thyroid stimulating hormone (TSH), causing an increase in thyroid hormone production [R]. An increase in thyroid hormone causes an increase in metabolism, leading to a number of health issues including weight loss [R].

TSHR controls not only the production of thyroid hormone but also the growth of thyroid cells [R] Excessive growth results in a goiter.

The SNP mutant of the TSHR gene was shown to be associated with increased susceptibility to Graves' disease [R], a common cause of hyperthyroidism that affects approximately 1% of the population [R].

Graves' disease is an autoimmune disease in which TSHR is stimulated by an antibody produced by the immune system, causing an increase in thyroid hormone production [R].

Graves' disease occurs statistically more often when the RS12101255 SNP is present in the TSHR gene [R].

Rs12101255 occurs in intron 1 of TSHR, a noncoding portion of the gene, but is shown to be in  linkage disequilibrium with an alteration to the coding region of TSHR, resulting in the increased incidence of Graves’ Disease [R].

The RS12101255 SNP is shown to increases susceptibility to Graves’ disease in specific European cohorts [R1, R2], and this trend has also been seen in Asian and South American populations [R].

The presence of the SNP may lead to a decrease in the presence of the full TSHR in favor of a split version of the protein [R]. This alteration of the TSHR protein favors antibody binding, thus causing an increase in thyroid hormone production.

Symptoms of Graves’ Disease include weight loss, fatigue, muscle weakness, decreased tolerance to heat, increased heart rate, nervousness or irritability, trouble sleeping, and a goiter [R].

     congenital hypothyroidism 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. Graves disease Genetics Home Reference provides information about Graves disease. tumors 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 disorders 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).

     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).