CACNA1A

CACNA1A is a human gene that encodes the alpha-1A subunit of the Cav2.1 voltage-gated calcium channel, the pore-forming component of P/Q-type calcium channels. These channels are essential for presynaptic calcium entry that triggers neurotransmitter release at many synapses. The CACNA1A gene is located on chromosome 19p13.3 and is widely expressed in the brain, with particularly high expression in the cerebellum.

The alpha-1A subunit has four homologous domains, each containing six transmembrane segments, forming the channel pore and voltage-sensing machinery. It associates with auxiliary beta and alpha-2/delta subunits that influence channel trafficking, kinetics, and regulation. Proper Cav2.1 function is critical for synaptic transmission, especially in cerebellar circuits involving Purkinje cells and cerebellar afferents.

Mutations in CACNA1A are linked to several neurological disorders. Familial hemiplegic migraine type 1 (FHM1) typically results from gain-of-function missense mutations that increase channel activity and neuronal excitability, contributing to migraine with aura and transient weakness. Episodic ataxia type 2 (EA2) usually arises from loss-of-function mutations that reduce Cav2.1 activity, leading to episodes of ataxia, vertigo, and neuromuscular symptoms. Spinocerebellar ataxia type 6 (SCA6) is caused by a CAG trinucleotide repeat expansion in CACNA1A, producing a polyglutamine tract that leads to progressive cerebellar degeneration and ataxia. Additional neurologic phenotypes, including some epilepsies, have been described in association with CACNA1A variants.

Diagnosis relies on genetic testing, with management being supportive and symptom-driven. EA2 can respond to acetazolamide, and some patients with FHM1 or EA2 may benefit from specific migraine or ataxia therapies; no disease-modifying treatment is currently available.