TSHR

The TSHR gene provides instructions for making a receptor that serves as a customized binding site for 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 is made in a gland at the base of the brain (the pituitary gland) and travels through the bloodstream to the thyroid gland. This hormone binds to the extracellular portion of the receptor, 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).

congenital hypothyroidism - caused by mutations in the TSHR gene

Several TSHR mutations have been identified in people who are insensitive (or resistant) to thyroid stimulating hormone. In some cases, this resistance causes congenital hypothyroidism. TSHR mutations change one of the chemical 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.

autoimmune disorders - associated with the TSHR gene

A major cause of thyroid disease is autoimmunity, in which the body's immune response turns against itself. The autoimmune response is triggered by a combination of genetic and environmental factors and includes the production of large Y-shaped proteins called antibodies or immunoglobulins. Antibodies that react against the body's own proteins are called autoantibodies. The presence of autoantibodies to the thyroid stimulating hormone receptor is an indication of autoimmune thyroid disease.

Graves disease is a common type of autoimmune thyroid disease. People with this disorder have autoantibodies that bind to the thyroid stimulating hormone receptor, causing continuous stimulation and an overproduction of thyroid hormones (hyperthyroidism). Graves disease causes a wide range of symptoms that can include anxiety, restlessness, and protruding eyes that may be red and swollen. Autoantibodies to the thyroid stimulating hormone receptor are present in more than 90 percent of people with Graves disease.

tumors - associated with the TSHR gene

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 in the tumor cells but not in cells from normal tissues.

Somatic TSHR 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 - caused by mutations in the TSHR gene

TSHR mutations can cause disorders in which the thyroid gland is overactive (hyperthyroidism). These mutations change one of the building blocks (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 mutations can lead to an enlarged thyroid gland (goiter) and symptoms of hyperthyroidism, such as a rapid heart beat. 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).