2.1. Autosomal Dominant Hypocalcemia

Mutations in the CASR gene can cause a condition called autosomal dominant hypocalcemia type 1, which is characterized by low levels of calcium in the blood (hypocalcemia). Some affected individuals also have a shortage of parathyroid hormone (hypoparathyroidism).

Most CASR gene mutations involved in this condition change single protein building blocks (amino acids) in the CaSR protein. The changes (called activating mutations) lead to an overactive CaSR that is more sensitive to calcium, meaning even low levels of calcium can trigger signaling. The overactive CaSR blocks the release of parathyroid hormone, which prevents the release of calcium into the blood. In addition, the overactive CaSR prevents reabsorption of calcium from the fluids filtered through the kidneys. Hypocalcemia can cause muscle cramping and seizures, although about half of people with this condition have no associated health problems.

2.2. Familial Isolated Hyperparathyroidism

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 amino acids in the CaSR protein. These genetic changes are called inactivating mutations because the altered CaSR protein 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 form of a similar condition called familial hypocalciuric hypercalcemia (described below).

2.3. Kidney Stones

Kidney stones

2.4. Other Disorders

Mutations in the CASR gene are involved in several other conditions associated with abnormal calcium levels. Inactivating mutations that lead to a reduction in CaSR function can 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 becomes apparent in infants under the age of 6 months. Affected babies often have overgrowth of one or more of their parathyroid glands (parathyroid hyperplasia), 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.