CACNA1S

The CACNA1S gene belongs to a family of genes that provide instructions for making calcium channels. These channels, which transport positively charged calcium atoms (ions) into cells, play a key role in a cell's ability to generate and transmit electrical signals.

The CACNA1S gene provides instructions for making calcium channels that are abundant in muscles used for movement (skeletal muscles). For the body to move normally, these muscles must tense (contract) and relax in a coordinated way. Muscle contractions are triggered by the flow of certain ions into muscle cells. Channels made with the CACNA1S protein control the transport of calcium ions into muscle cells and are part of the cellular machinery that initiates muscle contractions.

Channels made with the CACNA1S protein also activate a protein called ryanodine receptor 1 (produced by the RYR1 gene). Ryanodine receptor 1 forms a channel that releases stored calcium ions within muscle cells in response to certain signals. The resulting increase in calcium ion concentration stimulates muscle fibers to contract, allowing the body to move.

hypokalemic periodic paralysis - caused by mutations in the CACNA1S gene

At least four mutations in the CACNA1S gene have been identified in people with hypokalemic periodic paralysis. These 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.

malignant hyperthermia - increased risk from variations of the CACNA1S gene

CACNA1S mutations account for a very small percentage of all cases of malignant hyperthermia. Researchers have identified two mutations in the CACNA1S gene that are associated with an increased risk of this condition. One of these mutations replaces the amino acid arginine with the amino acid cysteine at protein position 1086 (written as Arg1086Cys); the other mutation replaces the amino acid arginine with the amino acid histidine at the same protein position (Arg1086His).

Genetic mutations likely cause channels made with the CACNA1S protein to 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 available calcium ions causes skeletal muscles to contract abnormally, which leads to muscle rigidity in people with malignant hyperthermia. An increase in calcium ion concentration also activates processes that generate heat (leading to increased body temperature) and produce excess acid (leading to acidosis).