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Snapshot: What is CACNA1A?

CACNA1A is a gene that contains the genetic information needed to make a transcription factor and a part of a calcium channel. The gene is mainly expressed in the brain and is pivotal to various neuronal functions such as muscle contractions, memory, learning, and gene expression. Mutations in CACNA1A has been associated with multiple disorders, collectively known as CACNA1A-related disorders. Examples of these disorders include:

Familial hemiplegic migraine type 1 (FHM1)

Episodic ataxia type 2 (EA2)

Spinocerebellar ataxia type 6 (SCA6).

The CACNA1A gene and the functions of its products

Most genes in the human genome produce one protein (monocistronic). Some genes, however, are unique in the sense that they produce two proteins from the same DNA. These genes are bicistronic, and CACNA1A is an example of it. The first protein CACNA1A encodes for is the α1A subunit. It makes up the inner portion of a calcium channel that allows calcium ions to pass through the membrane of a cell.

The calcium channels, along with other ion channels, plays an important role in maintaining a difference in electrical charge called the membrane potential. Changes in membrane potential are what allow neurons to activate themselves, conduct electrical signals and communicate with each other.

Calcium ions also play an important role in cell signaling. They are involved in cellular mechanisms such as gene expression, mitochondrial function and cell death. They also affect pathways that are involved in muscle contraction, release of neurotransmitters and hormone secretion.

The second protein CACNA1A encodes for is a transcription factor called α1ACT. Transcription factors control the expression of different genes, and the function of α1ACT have not been extensively studied. However, research has shown that α1ACT plays an important role in the early development of Purkinje cells.

CACNA1A-related disorders and proposed mechanisms of disease

Mutations in the CACNA1A gene can result in many disorders collectively called the CACNA1A-related disorders. A wide range of symptoms are associated with these disorders, including recurrent episodes of nystagmus (involuntary, rapid, and repetitive eye movements), vertigo and migraine, developmental delays, paroxysmal dystonia, ataxia, and hypotonia.

The mechanism of disease is hypothesized to be a loss of function or gain of toxic function of the calcium channels CACNA1A makes up. A loss of function is a genetic mutation that reduces or eliminates gene’s ability to function properly, whereas toxic gain of function is when a gene gains a function that might be harmful to a cell. These calcium channels are enriched in Purkinje cells, and its mutation could result in the dysregulation of calcium ions going in and out of the cells. Calcium ions play a pivotal role in neuronal signaling and its dysregulation can affect all of its functions mentioned above.

For instance, studies have found that in mouse models with FHM1 causing mutations, there are more influx of calcium into the cells. The neurons are more easily activated, neurotransmitters are more frequently released, potentially leading to disease symptoms. Studies have also shown that the loss of calcium channels in mouse models resulted in symptoms of ataxia and epilepsy. In SCA6, studies have shown that α1ACT alone or expressed outside of the CACNA1A gene could have toxic effects in mouse and fruit fly models. However, much of the disease mechanism remains elusive and further research is needed to understand the impact of the CACNA1A mutations.

If you would like to learn more about the CACNA1A gene, take a look at these resources by SCAsource, the CACNA1A Foundation, MedlinePlus, and the Children’s Hospital of Philadelphia.