CASR gene

The CASR gene is associated with:

  • autosomal dominant familial isolated hyperparathyroidism (FIHP)
  • autosomal dominant hypocalcemia (ADH)
  • benign familial hypocalciuric hypercalcemia (BFHH)
  • autosomal recessive neonatal severe hyperparathyroidism (NSHPT)

Additionally, there is preliminary evidence supporting a correlation with:

  • autosomal dominant idiopathic generalized epilepsy
  • chronic pancreatitis

The Normal Gene Function of CASR

The CASR gene provides instructions for making a protein called the calcium-sensing receptor (CaSR). Calcium molecules attach (bind) to 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 protein 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 large amounts of calcium bind to 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 protein 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. Increased calcium binding to CaSR in kidney cells blocks the reabsorption of calcium from the filtered fluids.

Familial isolated hyperparathyroidism

Familial isolated hyperparathyroidism is an inherited condition characterized by overactivity of the parathyroid glands (hyperparathyroidism). The four parathyroid glands are located in the neck, and they release a hormone called parathyroid hormone that regulates the amount of calcium in the blood. In familial isolated hyperparathyroidism, one or more overactive parathyroid glands release excess parathyroid hormone, which causes the levels of calcium in the blood to rise (hypercalcemia). Parathyroid hormone stimulates the removal of calcium from bone and the absorption of calcium from the diet, and the mineral is then released into the bloodstream.

In people with familial isolated hyperparathyroidism, the production of excess parathyroid hormone is caused by tumors that involve the parathyroid glands. Typically only one of the four parathyroid glands is affected, but in some people, more than one gland develops a tumor. The tumors are usually noncancerous (benign), in which case they are called adenomas. Rarely, people with familial isolated hyperparathyroidism develop a cancerous tumor called parathyroid carcinoma. Because the production of excess parathyroid hormone is caused by abnormalities of the parathyroid glands, familial isolated hyperparathyroidism is considered a form of primary hyperparathyroidism.

Disruption of the normal calcium balance resulting from overactive parathyroid glands causes many of the common signs and symptoms of familial isolated hyperparathyroidism, such as kidney stones, nausea, vomiting, high blood pressure (hypertension), weakness, and fatigue. Because calcium is removed from bones to be released into the bloodstream, hyperparathyroidism often causes thinning of the bones (osteoporosis). The age at which familial isolated hyperparathyroidism is diagnosed varies from childhood to adulthood. Often, the first indication of the condition is elevated calcium levels identified through a routine blood test, even though the affected individual may not yet have signs or symptoms of hyperparathyroidism or hypercalcemia.

Autosomal dominant hypocalcemia

Autosomal dominant hypocalcemia is characterized by low levels of calcium in the blood (hypocalcemia). Affected individuals can have an imbalance of other molecules in the blood as well, including too much phosphate (hyperphosphatemia) or too little magnesium (hypomagnesemia). Some people with autosomal dominant hypocalcemia also have low levels of a hormone called parathyroid hormone (hypoparathyroidism). This hormone is involved in the regulation of calcium levels in the blood. Abnormal levels of calcium and other molecules in the body can lead to a variety of signs and symptoms, although about half of affected individuals have no associated health problems.

The most common features of autosomal dominant hypocalcemia include muscle spasms in the hands and feet (carpopedal spasms) and muscle cramping, prickling or tingling sensations (paresthesias), or twitching of the nerves and muscles (neuromuscular irritability) in various parts of the body. More severely affected individuals develop seizures, usually in infancy or childhood. Sometimes, these symptoms occur only during episodes of illness or fever.

Some people with autosomal dominant hypocalcemia have high levels of calcium in their urine (hypercalciuria), which can lead to deposits of calcium in the kidneys (nephrocalcinosis) or the formation of kidney stones (nephrolithiasis). These conditions can damage the kidneys and impair their function. Sometimes, abnormal deposits of calcium form in the brain, typically in structures called basal ganglia, which help control movement.

A small percentage of severely affected individuals have features of a kidney disorder called Bartter syndrome in addition to hypocalcemia. These features can include a shortage of potassium (hypokalemia) and magnesium and a buildup of the hormone aldosterone (hyperaldosteronism) in the blood. The abnormal balance of molecules can raise the pH of the blood, which is known as metabolic alkalosis. The combination of features of these two conditions is sometimes referred to as autosomal dominant hypocalcemia with Bartter syndrome or Bartter syndrome type V.

There are two types of autosomal dominant hypocalcemia distinguished by their genetic cause. The signs and symptoms of the two types are generally the same. Autosomal dominant hypocalcemia is primarily caused by mutations in the CASR gene; these cases are known as type 1. A small percentage of cases, known as type 2, are caused by mutations in the GNA11 gene.

Other conditions:

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.