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Published on: June 2, 2014
Investigation of CACNA1I Cav3.3 Dysfunction in Hemiplegic Migraine
Neven Maksemous1, Claire D Blayney2, Heidi G Sutherland1
1Genomics Research Centre, The Centre for Genomics and Personalised Health, School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia.
Insights
Rare variants in the CACNA1I gene, encoding the Cav3.3 T-type calcium channel, are linked to familial hemiplegic migraine (FHM). These Cav3.3 channel variants show altered function, suggesting a new genetic cause for FHM.
Area of Science:
- Neurogenetics
- Molecular Neuroscience
- Ion Channel Physiology
Background:
- Familial hemiplegic migraine (FHM) is a severe neurogenetic disorder.
- Known FHM genes explain less than 20% of diagnostic cases, indicating other genetic factors are involved.
- T-type calcium channels, including Cav3.3, are implicated in various neurological conditions.
Purpose of the Study:
- To investigate the role of the CACNA1I gene and its encoded Cav3.3 T-type calcium channel in familial hemiplegic migraine (FHM).
- To identify potential genetic causes of FHM in patients negative for mutations in known FHM genes.
Main Methods:
- Whole-exome sequencing of 187 mutation-negative hemiplegic migraine (HM) cases.
- Burden testing of rare CACNA1I variants against population databases (gnomAD, UK Biobank).
- Patch-clamp electrophysiology to assess the biophysical properties of Cav3.3 variants.
Main Results:
- Rare variants in CACNA1I showed a statistically significant increased burden in HM cases compared to controls.
- Five Cav3.3 variants (p.R111G, p.M128L, p.D302G, p.R307H, p.Q1158H) exhibited altered biophysical properties compared to wild-type.
- The Cav3.3-Q1158H variant displayed significant functional differences, including reduced current density and altered kinetics.
- Cav3.3-R307H and -Q1158H variants showed altered conductance under acidosis and alkalosis conditions.
Conclusions:
- Rare variants in CACNA1I represent a potential genetic cause for familial hemiplegic migraine (FHM).
- Cav3.3 T-type calcium channel dysfunction, influenced by genetic variants, may contribute to FHM pathophysiology.
- This study expands the genetic landscape of FHM and highlights the role of T-type calcium channels.
Abstract:
Familial hemiplegic migraine (FHM) is a severe neurogenetic disorder for which three causal genes, CACNA1A, SCN1A, and ATP1A2, 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 CACNA1I gene encoding the T-type calcium channel Cav3.3. Burden testing of CACNA1I variants showed a statistically significant increase in allelic burden in the HM case group compared to gnomAD (OR = 2.30, P = 0.00005) and the UK Biobank (OR = 2.32, P = 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 CACNA1I may contribute to HM etiology.
