Investigation of CACNA1I Cav3.3 Dysfunction in Hemiplegic Migraine

• Published in: Frontiers in molecular neuroscience Vol. 15; p. 892820
• Main Authors: Maksemous, Neven, Blayney, Claire D, Sutherland, Heidi G, Smith, Robert A, Lea, Rod A, Tran, Kim Ngan, Ibrahim, Omar, McArthur, Jeffrey R, Haupt, Larisa M, Cader, M Zameel, Finol-Urdaneta, Rocio K, Adams, David J, Griffiths, Lyn R
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Research Foundation 19.07.2022; Frontiers Media S.A
• Subjects: Acidosis; Alkalosis; Ataxia; CACNA1I; Calcium channels; Calcium channels (T-type); Calcium channels (voltage-gated); Cav3.3; Electrophysiology; familial hemiplegic migraine; Gene expression; Genomics; Headache; hemiplegic migraine; ion channel; Kinetics; Migraine; migraine genetics; Molecular Neuroscience; Mutation; Proteins; Sodium channels (voltage-gated); Statistical analysis; Australia; United States > US; CACNA1I; Cav3.3; familial hemiplegic migraine; voltage gated calcium channels; ion channel; hemiplegic migraine; T-type calcium channels; migraine genetics
• ISSN: 1662-5099; 1662-5099
• DOI: 10.3389/fnmol.2022.892820

Familial hemiplegic migraine (FHM) is a severe neurogenetic disorder for which three causal genes, , , and , have been implicated. However, more than 80% of referred diagnostic cases of hemiplegic migraine (HM) are negative for exonic mutations in these known FHM genes, suggesting the involvement of other genes. Using whole-exome sequencing data from 187 mutation-negative HM cases, we identified rare variants in the gene encoding the T-type calcium channel Cav3.3. Burden testing of variants showed a statistically significant increase in allelic burden in the HM case group compared to gnomAD (OR = 2.30, = 0.00005) and the UK Biobank (OR = 2.32, = 0.0004) databases. Dysfunction in T-type calcium channels, including Cav3.3, has been implicated in a range of neurological conditions, suggesting a potential role in HM. Using patch-clamp electrophysiology, we compared the biophysical properties of five Cav3.3 variants (p.R111G, p.M128L, p.D302G, p.R307H, and p.Q1158H) to wild-type (WT) channels expressed in HEK293T cells. We observed numerous functional alterations across the channels with Cav3.3-Q1158H showing the greatest differences compared to WT channels, including reduced current density, right-shifted voltage dependence of activation and inactivation, and slower current kinetics. Interestingly, we also found significant differences in the conductance properties exhibited by the Cav3.3-R307H and -Q1158H variants compared to WT channels under conditions of acidosis and alkalosis. In light of these data, we suggest that rare variants in may contribute to HM etiology.