CACNA1I, encoding the Cav3.3 channel, is a gene associated with T-type calcium channels. These channels regulate low-threshold calcium spikes, burst firing, and rhythmic oscillations of neurons, being involved in sensory processing, sleep, and hormone/neurotransmitter release [1,3].

Research has identified various missense variants in CACNA1I in patients with neurodevelopmental phenotypes. For example, mutations like p.(Ile860Met), p.(Ile860Asn), p.(Ile1306Thr), and p.(Met1425Ile) lead to slowed kinetics of current activation, inactivation, and deactivation, along with hyperpolarizing shifts of voltage-dependence of activation and inactivation. This results in increased calcium influx, potentially causing calcium toxicity in neurons and contributing to neurodevelopmental disorders [1]. In a Swedish schizophrenia cohort, reduced CaV3.3 channel current density was associated with rare CACNA1I coding alleles from control subjects, while alleles from schizophrenia patients encoded channels with altered voltage responses [4]. Also, rare variants in CACNA1I may contribute to the etiology of hemiplegic migraine as they show functional alterations in Cav3.3 channels [2,5].

In conclusion, CACNA1I plays a crucial role in neuronal function through its regulation of T-type calcium channels. Studies on its variants in patients with neurodevelopmental disorders, schizophrenia, and hemiplegic migraine have provided insights into its function in these disease areas. Understanding the role of CACNA1I can potentially offer new directions for diagnosing and treating these neurological conditions.

References:

1. El Ghaleb, Yousra, Schneeberger, Pauline E, Fernández-Quintero, Monica L, Kutsche, Kerstin, Flucher, Bernhard E. . CACNA1I gain-of-function mutations differentially affect channel gating and cause neurodevelopmental disorders. In Brain : a journal of neurology, 144, 2092-2106. doi:10.1093/brain/awab101. https://pubmed.ncbi.nlm.nih.gov/33704440/

2. Maksemous, Neven, Blayney, Claire D, Sutherland, Heidi G, Adams, David J, Griffiths, Lyn R. 2022. Investigation of CACNA1I Cav3.3 Dysfunction in Hemiplegic Migraine. In Frontiers in molecular neuroscience, 15, 892820. doi:10.3389/fnmol.2022.892820. https://pubmed.ncbi.nlm.nih.gov/35928792/

3. El Ghaleb, Yousra, Flucher, Bernhard E. . CaV3.3 Channelopathies. In Handbook of experimental pharmacology, 279, 263-288. doi:10.1007/164_2022_631. https://pubmed.ncbi.nlm.nih.gov/36592228/

4. Baez-Nieto, David, Allen, Andrew, Akers-Campbell, Seth, Lipscombe, Diane, Pan, Jen Q. . Analysing an allelic series of rare missense variants of CACNA1I in a Swedish schizophrenia cohort. In Brain : a journal of neurology, 145, 1839-1853. doi:10.1093/brain/awab443. https://pubmed.ncbi.nlm.nih.gov/34919654/

5. Maksemous, Neven, Harder, Aster V E, Ibrahim, Omar, van den Maagdenberg, Arn M J M, Griffiths, Lyn R. 2023. Whole Exome Sequencing of Hemiplegic Migraine Patients Shows an Increased Burden of Missense Variants in CACNA1H and CACNA1I Genes. In Molecular neurobiology, 60, 3034-3043. doi:10.1007/s12035-023-03255-5. https://pubmed.ncbi.nlm.nih.gov/36786913/