CACNA1S

CACNA1S gene mutations account for a very small percentage of all cases of malignant hyperthermia. Malignant hyperthermia is a severe reaction to particular anesthetic drugs that are often used during surgery and other invasive procedures. The reaction involves a high fever (hyperthermia), a rapid heart rate, muscle rigidity, breakdown of muscle fibers (rhabdomyolysis), and increased acid levels in the blood and other tissues (acidosis). Complications can be life-threatening without prompt treatment. Researchers have identified several mutations in the CACNA1S gene that are associated with an increased risk of this condition. These mutations replace single amino acids in the CACNA1S protein.

Channels made with the altered CACNA1S proteins likely activate the RYR1 channel improperly in response to certain drugs (particularly some anesthetics and a type of muscle relaxant used during surgery). As a result, large amounts of calcium ions are released from storage within muscle cells. An overabundance of calcium ions activates processes that generate heat (leading to increased body temperature) and produce excess acid (leading to acidosis). An increase in calcium ion concentration also causes skeletal muscles to contract abnormally, which leads to muscle rigidity.

At least 11 mutations in the CACNA1S gene have been identified in people with hypokalemic periodic paralysis, a condition that causes episodes of extreme muscle weakness, usually in the arms and legs. CACNA1S gene mutations cause up to 70 percent of all cases of this disorder.

Mutations in the CACNA1S gene change single protein building blocks (amino acids) used to make the CACNA1S protein, which alters the structure and function of calcium channels in skeletal muscle cells. The altered channels open more slowly than usual, reducing the flow of calcium ions into these cells. This disruption in calcium ion transport prevents muscles from contracting normally. It is unclear precisely how these changes lead to episodes of muscle weakness in people with hypokalemic periodic paralysis.