Investigation of CACNA1I Cav3.3 Dysfunction in Hemiplegic Migraine
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...
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| Format: | Article |
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Frontiers Media S.A.
2022-07-01
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| Series: | Frontiers in Molecular Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnmol.2022.892820/full |
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| author | Neven Maksemous Claire D. Blayney Heidi G. Sutherland Robert A. Smith Rod A. Lea Kim Ngan Tran Omar Ibrahim Jeffrey R. McArthur Larisa M. Haupt M. Zameel Cader Rocio K. Finol-Urdaneta David J. Adams Lyn R. Griffiths |
| author_facet | Neven Maksemous Claire D. Blayney Heidi G. Sutherland Robert A. Smith Rod A. Lea Kim Ngan Tran Omar Ibrahim Jeffrey R. McArthur Larisa M. Haupt M. Zameel Cader Rocio K. Finol-Urdaneta David J. Adams Lyn R. Griffiths |
| author_sort | Neven Maksemous |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T22:38:32Z |
| format | Article |
| id | doaj.art-483ec272a040492885598e5a29002b7f |
| institution | Directory Open Access Journal |
| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-12-10T22:38:32Z |
| publishDate | 2022-07-01 |
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| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-483ec272a040492885598e5a29002b7f2022-12-22T01:30:46ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992022-07-011510.3389/fnmol.2022.892820892820Investigation of CACNA1I Cav3.3 Dysfunction in Hemiplegic MigraineNeven Maksemous0Claire D. Blayney1Heidi G. Sutherland2Robert A. Smith3Rod A. Lea4Kim Ngan Tran5Omar Ibrahim6Jeffrey R. McArthur7Larisa M. Haupt8M. Zameel Cader9Rocio K. Finol-Urdaneta10David J. Adams11Lyn R. Griffiths12Genomics Research Centre, The Centre for Genomics and Personalised Health, School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, AustraliaIllawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW, AustraliaGenomics Research Centre, The Centre for Genomics and Personalised Health, School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, AustraliaGenomics Research Centre, The Centre for Genomics and Personalised Health, School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, AustraliaGenomics Research Centre, The Centre for Genomics and Personalised Health, School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, AustraliaGenomics Research Centre, The Centre for Genomics and Personalised Health, School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, AustraliaGenomics Research Centre, The Centre for Genomics and Personalised Health, School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, AustraliaIllawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW, AustraliaGenomics Research Centre, The Centre for Genomics and Personalised Health, School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, AustraliaWeatherall Institute of Molecular Medicine, University of Oxford, Oxford, United KingdomIllawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW, AustraliaIllawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW, AustraliaGenomics Research Centre, The Centre for Genomics and Personalised Health, School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, AustraliaFamilial 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.https://www.frontiersin.org/articles/10.3389/fnmol.2022.892820/fullhemiplegic migrainefamilial hemiplegic migrainemigraine geneticsion channelCACNA1ICav3.3 |
| spellingShingle | Neven Maksemous Claire D. Blayney Heidi G. Sutherland Robert A. Smith Rod A. Lea Kim Ngan Tran Omar Ibrahim Jeffrey R. McArthur Larisa M. Haupt M. Zameel Cader Rocio K. Finol-Urdaneta David J. Adams Lyn R. Griffiths Investigation of CACNA1I Cav3.3 Dysfunction in Hemiplegic Migraine Frontiers in Molecular Neuroscience hemiplegic migraine familial hemiplegic migraine migraine genetics ion channel CACNA1I Cav3.3 |
| title | Investigation of CACNA1I Cav3.3 Dysfunction in Hemiplegic Migraine |
| title_full | Investigation of CACNA1I Cav3.3 Dysfunction in Hemiplegic Migraine |
| title_fullStr | Investigation of CACNA1I Cav3.3 Dysfunction in Hemiplegic Migraine |
| title_full_unstemmed | Investigation of CACNA1I Cav3.3 Dysfunction in Hemiplegic Migraine |
| title_short | Investigation of CACNA1I Cav3.3 Dysfunction in Hemiplegic Migraine |
| title_sort | investigation of cacna1i cav3 3 dysfunction in hemiplegic migraine |
| topic | hemiplegic migraine familial hemiplegic migraine migraine genetics ion channel CACNA1I Cav3.3 |
| url | https://www.frontiersin.org/articles/10.3389/fnmol.2022.892820/full |
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