STAC3

STAC3 disorder

At least five mutations in the STAC3 gene have been found to cause STAC3 disorder (formerly known as Native American myopathy). This condition is a muscle disorder characterized by weakness, droopy eyelids (ptosis) and other distinctive facial features, joint deformities (contractures), and increased risk of a condition known as malignant hyperthermia, which is a severe reaction to particular anesthetic drugs that are often used during surgery and other invasive procedures.

Mutations in the STAC3 gene reduce the amount or impair the function of the STAC3 protein. Although the mechanism is unclear, studies show that a shortage of working STAC3 protein affects the function of DHPR and prevents the release of calcium ions by RYR1 channels, resulting in a buildup of calcium in storage. A disruption in calcium ion release prevents muscles from contracting normally, leading to the muscle weakness characteristic of STAC3 disorder.

It is unclear how these STAC3 gene mutations lead to malignant hyperthermia in susceptible individuals. Mutations in other genes related to malignant hyperthermia activate the RYR1 channel improperly in response to certain drugs. 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. An increase in calcium ion concentration also activates processes that generate heat (leading to increased body temperature) and produce excess acid (leading to acidosis). It is unknown if STAC3 gene mutations have a similar effect on RYR1 channel activity.