CASR

The CASR gene provides instructions for making a protein called the calcium-sensing receptor (CaSR). Calcium molecules attach (bind) to the CaSR, which allows this protein to monitor and regulate the amount of calcium in the blood. The receptor is turned on (activated) when a certain concentration of calcium is reached, and the activated receptor sends signals to block processes that increase the amount of calcium in the blood.

The CaSR is found in abundance in cells of the parathyroid glands. The parathyroid glands produce and release a hormone called parathyroid hormone that works to increase the levels of calcium in the blood. When calcium binds to the CaSR in the parathyroid glands, the production of parathyroid hormone is blocked, which prevents the release of more calcium into the blood. CaSR signaling also blocks the growth and division (proliferation) of cells that make up the parathyroid glands.

The CaSR is also found in kidney cells. Kidneys filter fluid and waste products in the body and can reabsorb needed nutrients and release them back into the blood. Calcium binding to the CaSR in kidney cells blocks the reabsorption of calcium from the filtered fluids.

familial isolated hyperparathyroidism - caused by mutations in the CASR gene

Mutations in the CASR gene have been found in some people with familial isolated hyperparathyroidism, a condition characterized by overactivity of the parathyroid glands (primary hyperparathyroidism). Primary hyperparathyroidism disrupts the normal balance of calcium in the blood, which can lead to kidney stones, thinning of the bones (osteoporosis), nausea, vomiting, high blood pressure (hypertension), weakness, and fatigue in people with familial isolated hyperparathyroidism. This condition is caused by changes to one copy of the gene in each cell. The CASR gene mutations associated with this condition change single protein building blocks (amino acids) in the CaSR. The altered CaSR is less sensitive to calcium and therefore requires an abnormally high concentration of calcium to trigger signaling. As a result, parathyroid hormone is produced even when the concentration of calcium in the blood is elevated, allowing the calcium levels to continue to rise. In addition, parathyroid cells may proliferate without control, which occasionally causes enlargement of the parathyroid glands in people with familial isolated hyperparathyroidism. Overproduction of parathyroid hormone from these abnormal glands may further stimulate the release of calcium into the blood. The high levels of calcium cause the signs and symptoms of familial isolated hyperparathyroidism.

Some researchers believe that familial isolated hyperparathyroidism caused by CASR gene mutations is a more severe presentation of a similar condition called familial hypocalciuric hypercalcemia (described below).

other disorders - caused by mutations in the CASR gene

Mutations in the CASR gene are involved in several other conditions associated with abnormal calcium balance. Genetic changes that lead to a reduction in CaSR function cause familial hypocalciuric hypercalcemia. This condition is characterized by high levels of calcium in the blood (hypercalcemia) and low levels of calcium in the urine (hypocalciuria), but affected individuals typically have no symptoms related to the condition. Rarely, affected individuals have enlarged parathyroid glands and slightly elevated levels of parathyroid hormone. Like familial isolated hyperparathyroidism, this condition is caused by mutation of a single copy of the CASR gene.

A more serious condition called neonatal severe hyperparathyroidism is caused by genetic mutations that lead to very little or no CaSR function. In people with this condition, both copies of the CASR gene are altered. Neonatal severe hyperparathyroidism is a potentially fatal condition that occurs in infants under 6 months of age. Affected babies often have noncancerous tumors (called adenomas) involving one or more of their parathyroid glands, causing high levels of parathyroid hormone in their blood. The excess hormone abnormally stimulates the release of calcium into the blood, causing hypercalcemia. The calcium is often removed from bone, resulting in skeletal abnormalities. The extreme hypercalcemia in these individuals can lead to neurological problems because the excess calcium interferes with nerve signaling.

In contrast, autosomal dominant hypocalcemia is caused by mutations that lead to an overactive CaSR and is characterized by low levels of calcium in the blood (hypocalcemia) and excess calcium in the urine (hypercalciuria). The overactive CaSR blocks the release of parathyroid hormone, which prevents the release of calcium into the blood and the reabsorption of calcium from the fluids filtered through the kidneys. Hypocalcemia causes seizures in a small number of affected individuals, and hypercalciuria can cause kidney problems, such as kidney stones and impaired kidney function.