Cargando…
CACNA1A Mutations Associated With Epilepsies and Their Molecular Sub-Regional Implications
PURPOSE: Previously, mutations in the voltage-gated calcium channel subunit alpha1 A (CACNA1A) gene have been reported to be associated with paroxysmal disorders, typically as episodic ataxia type 2. To determine the relationship between CACNA1A and epilepsies and the role of molecular sub-regional...
Autores principales: | , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9116572/ https://www.ncbi.nlm.nih.gov/pubmed/35600082 http://dx.doi.org/10.3389/fnmol.2022.860662 |
_version_ | 1784710140631449600 |
---|---|
author | Li, Xue-Lian Li, Zong-Jun Liang, Xiao-Yu Liu, De-Tian Jiang, Mi Gao, Liang-Di Li, Huan Tang, Xue-Qing Shi, Yi-Wu Li, Bing-Mei He, Na Li, Bin Bian, Wen-Jun Yi, Yong-Hong Cheng, Chuan-Fang Wang, Jie |
author_facet | Li, Xue-Lian Li, Zong-Jun Liang, Xiao-Yu Liu, De-Tian Jiang, Mi Gao, Liang-Di Li, Huan Tang, Xue-Qing Shi, Yi-Wu Li, Bing-Mei He, Na Li, Bin Bian, Wen-Jun Yi, Yong-Hong Cheng, Chuan-Fang Wang, Jie |
author_sort | Li, Xue-Lian |
collection | PubMed |
description | PURPOSE: Previously, mutations in the voltage-gated calcium channel subunit alpha1 A (CACNA1A) gene have been reported to be associated with paroxysmal disorders, typically as episodic ataxia type 2. To determine the relationship between CACNA1A and epilepsies and the role of molecular sub-regional on the phenotypic heterogeneity. METHODS: Trio-based whole-exome sequencing was performed in 318 cases with partial epilepsy and 150 cases with generalized epilepsy. We then reviewed all previously reported CACNA1A mutations and analyzed the genotype-phenotype correlations with molecular sub-regional implications. RESULTS: We identified 12 CACNA1A mutations in ten unrelated cases of epilepsy, including four de novo null mutations (c.2963_2964insG/p.Gly989Argfs*78, c.3089 + 1G > A, c.4755 + 1G > T, and c.6340-1G > A), four de novo missense mutations (c.203G > T/p.Arg68Leu, c.3965G > A/p.Gly1322Glu, c.5032C > T/p.Arg1678Cys, and c.5393C > T/p.Ser1798Leu), and two pairs of compound heterozygous missense mutations (c.4891A > G/p.Ile1631Val& c.5978C > T/p.Pro1993Leu and c.3233C > T/p.Ser1078Leu&c.6061G > A/p.Glu2021Lys). The eight de novo mutations were evaluated as pathogenic or likely pathogenic mutations according to the criteria of American College of Medical Genetics and Genomics (ACMG). The frequencies of the compound heterozygous CACNA1A mutations identified in this cohort were significantly higher than that in the controls of East Asian and all populations (P = 7.30 × 10(–4), P = 2.53 × 10(–4)). All of the ten cases were ultimately seizure-free after antiepileptic treatment, although frequent epileptic seizures were observed in four cases. Further analysis revealed that episodic ataxia type 2 (EA2) had a tendency of higher frequency of null mutations than epilepsies. The missense mutations in severe epileptic phenotypes were more frequently located in the pore region than those in milder epileptic phenotypes (P = 1.67 × 10(–4)); de novo mutations in the epilepsy with intellectual disability (ID) had a higher percentage than those in the epilepsy without ID (P = 1.92 × 10(–3)). CONCLUSION: This study suggested that CACNA1A mutations were potentially associated with pure epilepsy and the spectrum of epileptic phenotypes potentially ranged from the mild form of epilepsies such as absence epilepsy or partial epilepsy, to the severe form of developmental epileptic encephalopathy. The clinical phenotypes variability is potentially associated with the molecular sub-regional of the mutations. |
format | Online Article Text |
id | pubmed-9116572 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-91165722022-05-19 CACNA1A Mutations Associated With Epilepsies and Their Molecular Sub-Regional Implications Li, Xue-Lian Li, Zong-Jun Liang, Xiao-Yu Liu, De-Tian Jiang, Mi Gao, Liang-Di Li, Huan Tang, Xue-Qing Shi, Yi-Wu Li, Bing-Mei He, Na Li, Bin Bian, Wen-Jun Yi, Yong-Hong Cheng, Chuan-Fang Wang, Jie Front Mol Neurosci Molecular Neuroscience PURPOSE: Previously, mutations in the voltage-gated calcium channel subunit alpha1 A (CACNA1A) gene have been reported to be associated with paroxysmal disorders, typically as episodic ataxia type 2. To determine the relationship between CACNA1A and epilepsies and the role of molecular sub-regional on the phenotypic heterogeneity. METHODS: Trio-based whole-exome sequencing was performed in 318 cases with partial epilepsy and 150 cases with generalized epilepsy. We then reviewed all previously reported CACNA1A mutations and analyzed the genotype-phenotype correlations with molecular sub-regional implications. RESULTS: We identified 12 CACNA1A mutations in ten unrelated cases of epilepsy, including four de novo null mutations (c.2963_2964insG/p.Gly989Argfs*78, c.3089 + 1G > A, c.4755 + 1G > T, and c.6340-1G > A), four de novo missense mutations (c.203G > T/p.Arg68Leu, c.3965G > A/p.Gly1322Glu, c.5032C > T/p.Arg1678Cys, and c.5393C > T/p.Ser1798Leu), and two pairs of compound heterozygous missense mutations (c.4891A > G/p.Ile1631Val& c.5978C > T/p.Pro1993Leu and c.3233C > T/p.Ser1078Leu&c.6061G > A/p.Glu2021Lys). The eight de novo mutations were evaluated as pathogenic or likely pathogenic mutations according to the criteria of American College of Medical Genetics and Genomics (ACMG). The frequencies of the compound heterozygous CACNA1A mutations identified in this cohort were significantly higher than that in the controls of East Asian and all populations (P = 7.30 × 10(–4), P = 2.53 × 10(–4)). All of the ten cases were ultimately seizure-free after antiepileptic treatment, although frequent epileptic seizures were observed in four cases. Further analysis revealed that episodic ataxia type 2 (EA2) had a tendency of higher frequency of null mutations than epilepsies. The missense mutations in severe epileptic phenotypes were more frequently located in the pore region than those in milder epileptic phenotypes (P = 1.67 × 10(–4)); de novo mutations in the epilepsy with intellectual disability (ID) had a higher percentage than those in the epilepsy without ID (P = 1.92 × 10(–3)). CONCLUSION: This study suggested that CACNA1A mutations were potentially associated with pure epilepsy and the spectrum of epileptic phenotypes potentially ranged from the mild form of epilepsies such as absence epilepsy or partial epilepsy, to the severe form of developmental epileptic encephalopathy. The clinical phenotypes variability is potentially associated with the molecular sub-regional of the mutations. Frontiers Media S.A. 2022-05-04 /pmc/articles/PMC9116572/ /pubmed/35600082 http://dx.doi.org/10.3389/fnmol.2022.860662 Text en Copyright © 2022 Li, Li, Liang, Liu, Jiang, Gao, Li, Tang, Shi, Li, He, Li, Bian, Yi, Cheng and Wang. 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 Li, Xue-Lian Li, Zong-Jun Liang, Xiao-Yu Liu, De-Tian Jiang, Mi Gao, Liang-Di Li, Huan Tang, Xue-Qing Shi, Yi-Wu Li, Bing-Mei He, Na Li, Bin Bian, Wen-Jun Yi, Yong-Hong Cheng, Chuan-Fang Wang, Jie CACNA1A Mutations Associated With Epilepsies and Their Molecular Sub-Regional Implications |
title | CACNA1A Mutations Associated With Epilepsies and Their Molecular Sub-Regional Implications |
title_full | CACNA1A Mutations Associated With Epilepsies and Their Molecular Sub-Regional Implications |
title_fullStr | CACNA1A Mutations Associated With Epilepsies and Their Molecular Sub-Regional Implications |
title_full_unstemmed | CACNA1A Mutations Associated With Epilepsies and Their Molecular Sub-Regional Implications |
title_short | CACNA1A Mutations Associated With Epilepsies and Their Molecular Sub-Regional Implications |
title_sort | cacna1a mutations associated with epilepsies and their molecular sub-regional implications |
topic | Molecular Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9116572/ https://www.ncbi.nlm.nih.gov/pubmed/35600082 http://dx.doi.org/10.3389/fnmol.2022.860662 |
work_keys_str_mv | AT lixuelian cacna1amutationsassociatedwithepilepsiesandtheirmolecularsubregionalimplications AT lizongjun cacna1amutationsassociatedwithepilepsiesandtheirmolecularsubregionalimplications AT liangxiaoyu cacna1amutationsassociatedwithepilepsiesandtheirmolecularsubregionalimplications AT liudetian cacna1amutationsassociatedwithepilepsiesandtheirmolecularsubregionalimplications AT jiangmi cacna1amutationsassociatedwithepilepsiesandtheirmolecularsubregionalimplications AT gaoliangdi cacna1amutationsassociatedwithepilepsiesandtheirmolecularsubregionalimplications AT lihuan cacna1amutationsassociatedwithepilepsiesandtheirmolecularsubregionalimplications AT tangxueqing cacna1amutationsassociatedwithepilepsiesandtheirmolecularsubregionalimplications AT shiyiwu cacna1amutationsassociatedwithepilepsiesandtheirmolecularsubregionalimplications AT libingmei cacna1amutationsassociatedwithepilepsiesandtheirmolecularsubregionalimplications AT hena cacna1amutationsassociatedwithepilepsiesandtheirmolecularsubregionalimplications AT libin cacna1amutationsassociatedwithepilepsiesandtheirmolecularsubregionalimplications AT bianwenjun cacna1amutationsassociatedwithepilepsiesandtheirmolecularsubregionalimplications AT yiyonghong cacna1amutationsassociatedwithepilepsiesandtheirmolecularsubregionalimplications AT chengchuanfang cacna1amutationsassociatedwithepilepsiesandtheirmolecularsubregionalimplications AT wangjie cacna1amutationsassociatedwithepilepsiesandtheirmolecularsubregionalimplications |