ATP1A2

The ATP1A2 gene provides instructions for making one part (the alpha-2 subunit) of a protein known as a Na+/K+ ATPase. This protein uses energy from a molecule called adenosine triphosphate (ATP) to transport charged atoms (ions) into and out of cells. Specifically, it pumps sodium ions (Na+) out of cells and potassium ions (K+) into cells.

The Na+/K+ ATPase plays a critical role in the normal function of nerve cells (neurons). Communication between neurons depends on chemicals called neurotransmitters. To relay signals, a neuron releases neurotransmitters, which attach to receptor proteins on neighboring neurons. After the neurotransmitters have had their effect, they detach from their receptors and are removed from the spaces between neurons. This process is carefully regulated to ensure that signals are transmitted accurately throughout the nervous system. The Na+/K+ ATPase helps regulate this process by clearing neurotransmitters from the spaces between neurons. This protein also removes excess potassium ions from these spaces.

familial hemiplegic migraine - caused by mutations in the ATP1A2 gene

More than 20 mutations in the ATP1A2 gene have been identified in people with familial hemiplegic migraine type 2 (FHM2). Most of these mutations change single protein building blocks (amino acids) in the Na+/K+ ATPase protein. Some mutations impair the protein's ability to transport ions. Others prevent the production of any protein from one copy of the ATP1A2 gene in each cell. As a result, less potassium is pumped into neurons, less sodium is pumped out of these cells, and neurotransmitters spend more time in the spaces between neurons. The resulting changes in signaling in the brain make people with FHM2 more susceptible to developing these severe headaches.

other disorders - caused by mutations in the ATP1A2 gene

ATP1A2 mutations appear to be a relatively common cause of sporadic hemiplegic migraine (SHM). The signs and symptoms of this condition are identical to those of familial hemiplegic migraine; however, sporadic hemiplegic migraine occurs in people with no family history of the condition.

A change in the ATP1A2 gene has also been found to cause alternating hemiplegia of childhood (AHC). This condition is characterized by recurrent episodes of temporary paralysis, often affecting one side of the body (hemiplegia). In some cases, the paralysis alternates from one side to the other or affects both sides of the body at the same time. These episodes usually begin in infancy or early childhood, and paralysis lasts from minutes to days. Other symptoms of this condition can include involuntary movements, seizures, migraine headaches, and a decline in brain function over time.

The single ATP1A2 mutation known to be associated with alternating hemiplegia of childhood changes one protein building block (amino acid) in the Na+/K+ ATPase protein. Specifically, the mutation replaces the amino acid threonine with the amino acid asparagine at protein position 378 (written as Thr378Asn or T378N). This genetic change probably impairs the protein's ability to transport ions, although it is unclear how the mutation leads to the specific features of alternating hemiplegia of childhood.