CACNA1I encodes the Cav3.3 channel, a member of the T-type calcium channel family (Cav3.1-Cav3.3). These channels regulate low-threshold calcium spikes, burst firing, and rhythmic oscillations of neurons, and are involved in sensory processing, sleep, and hormone and neurotransmitter release [1,3].

Gain-of-function mutations in CACNA1I can cause neurodevelopmental disorders. Mutations such as p.(Ile860Met), p.(Ile860Asn), p.(Ile1306Thr), and p.(Met1425Ile) lead to slowed kinetics of current activation, inactivation, and deactivation, and hyperpolarizing shifts of voltage-dependence of activation and inactivation. This results in increased calcium influx, potentially causing calcium toxicity in neurons and neuronal hyper-excitability, which can explain symptoms like seizures [1].

In a Swedish schizophrenia cohort, rare CACNA1I alleles from schizophrenia patients encoded CaV3.3 channels with altered responses to voltages, while rare alleles from control subjects were associated with reduced CaV3.3 channel current density. Reduced CaV3.3 function may protect against schizophrenia risk in rare cases [4]. Also, there is evidence suggesting an increased burden of missense variants in CACNA1I in hemiplegic migraine patients, and some studies have associated it with schizophrenia in Chinese populations [2,5,6,7].

In conclusion, CACNA1I is crucial for normal neuronal function through its role in T-type calcium channel activity. Studies on its gain-and loss-of-function mutations, especially in relation to neurodevelopmental disorders and schizophrenia, have provided insights into the molecular mechanisms underlying these diseases. Understanding CACNA1I can potentially lead to new therapeutic strategies for these neurological conditions.