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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...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9345121/ https://www.ncbi.nlm.nih.gov/pubmed/35928792 http://dx.doi.org/10.3389/fnmol.2022.892820 |
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author | 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. |
author_facet | 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. |
author_sort | Maksemous, Neven |
collection | PubMed |
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. |
format | Online Article Text |
id | pubmed-9345121 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-93451212022-08-03 Investigation of CACNA1I Cav3.3 Dysfunction in Hemiplegic Migraine 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. Front Mol Neurosci Molecular Neuroscience 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. Frontiers Media S.A. 2022-07-19 /pmc/articles/PMC9345121/ /pubmed/35928792 http://dx.doi.org/10.3389/fnmol.2022.892820 Text en Copyright © 2022 Maksemous, Blayney, Sutherland, Smith, Lea, Tran, Ibrahim, McArthur, Haupt, Cader, Finol-Urdaneta, Adams and Griffiths. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Molecular Neuroscience 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. Investigation of CACNA1I Cav3.3 Dysfunction in Hemiplegic Migraine |
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 | Molecular Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9345121/ https://www.ncbi.nlm.nih.gov/pubmed/35928792 http://dx.doi.org/10.3389/fnmol.2022.892820 |
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