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Dravet syndrome-associated mutations in GABRA1, GABRB2 and GABRG2 define the genetic landscape of defects of GABA(A) receptors

Dravet syndrome is a rare, catastrophic epileptic encephalopathy that begins in the first year of life, usually with febrile or afebrile hemiclonic or generalized tonic–clonic seizures followed by status epilepticus. De novo variants in genes that mediate synaptic transmission such as SCN1A and PCDH...

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Autores principales: Hernandez, Ciria C, Tian, XiaoJuan, Hu, Ningning, Shen, Wangzhen, Catron, Mackenzie A, Yang, Ying, Chen, Jiaoyang, Jiang, Yuwu, Zhang, Yuehua, Macdonald, Robert L
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176149/
https://www.ncbi.nlm.nih.gov/pubmed/34095830
http://dx.doi.org/10.1093/braincomms/fcab033
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author Hernandez, Ciria C
Tian, XiaoJuan
Hu, Ningning
Shen, Wangzhen
Catron, Mackenzie A
Yang, Ying
Chen, Jiaoyang
Jiang, Yuwu
Zhang, Yuehua
Macdonald, Robert L
author_facet Hernandez, Ciria C
Tian, XiaoJuan
Hu, Ningning
Shen, Wangzhen
Catron, Mackenzie A
Yang, Ying
Chen, Jiaoyang
Jiang, Yuwu
Zhang, Yuehua
Macdonald, Robert L
author_sort Hernandez, Ciria C
collection PubMed
description Dravet syndrome is a rare, catastrophic epileptic encephalopathy that begins in the first year of life, usually with febrile or afebrile hemiclonic or generalized tonic–clonic seizures followed by status epilepticus. De novo variants in genes that mediate synaptic transmission such as SCN1A and PCDH19 are often associated with Dravet syndrome. Recently, GABA(A) receptor subunit genes (GABRs) encoding α1 (GABRA1), β3 (GABRB3) and γ2 (GABRG2), but not β2 (GABRB2) or β1 (GABRB1), subunits are frequently associated with Dravet syndrome or Dravet syndrome-like phenotype. We performed next generation sequencing on 870 patients with Dravet syndrome and identified nine variants in three different GABRs. Interestingly, the variants were all in genes encoding the most common GABA(A) receptor, the α1β2γ2 receptor. Mutations in GABRA1 (c.644T>C, p. L215P; c.640C>T, p. R214C; c.859G>A; V287I; c.641G>A, p. R214H) and GABRG2 (c.269C>G, p. T90R; c.1025C>T, p. P342L) presented as de novo cases, while in GABRB2 two variants were de novo (c.992T>C, p. F331S; c.542A>T, p. Y181F) and one was autosomal dominant and inherited from the maternal side (c.990_992del, p.330_331del). We characterized the effects of these GABR variants on GABA(A) receptor biogenesis and channel function. We found that defects in receptor gating were the common deficiency of GABRA1 and GABRB2 Dravet syndrome variants, while mainly trafficking defects were found with the GABRG2 (c.269C>G, p. T90R) variant. It seems that variants in α1 and β2 subunits are less tolerated than in γ2 subunits, since variant α1 and β2 subunits express well but were functionally deficient. This suggests that all of these GABR variants are all targeting GABR genes that encode the assembled α1β2γ2 receptor, and regardless of which of the three subunits are mutated, variants in genes coding for α1, β2 and γ2 receptor subunits make them candidate causative genes in the pathogenesis of Dravet syndrome.
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spelling pubmed-81761492021-06-04 Dravet syndrome-associated mutations in GABRA1, GABRB2 and GABRG2 define the genetic landscape of defects of GABA(A) receptors Hernandez, Ciria C Tian, XiaoJuan Hu, Ningning Shen, Wangzhen Catron, Mackenzie A Yang, Ying Chen, Jiaoyang Jiang, Yuwu Zhang, Yuehua Macdonald, Robert L Brain Commun Original Article Dravet syndrome is a rare, catastrophic epileptic encephalopathy that begins in the first year of life, usually with febrile or afebrile hemiclonic or generalized tonic–clonic seizures followed by status epilepticus. De novo variants in genes that mediate synaptic transmission such as SCN1A and PCDH19 are often associated with Dravet syndrome. Recently, GABA(A) receptor subunit genes (GABRs) encoding α1 (GABRA1), β3 (GABRB3) and γ2 (GABRG2), but not β2 (GABRB2) or β1 (GABRB1), subunits are frequently associated with Dravet syndrome or Dravet syndrome-like phenotype. We performed next generation sequencing on 870 patients with Dravet syndrome and identified nine variants in three different GABRs. Interestingly, the variants were all in genes encoding the most common GABA(A) receptor, the α1β2γ2 receptor. Mutations in GABRA1 (c.644T>C, p. L215P; c.640C>T, p. R214C; c.859G>A; V287I; c.641G>A, p. R214H) and GABRG2 (c.269C>G, p. T90R; c.1025C>T, p. P342L) presented as de novo cases, while in GABRB2 two variants were de novo (c.992T>C, p. F331S; c.542A>T, p. Y181F) and one was autosomal dominant and inherited from the maternal side (c.990_992del, p.330_331del). We characterized the effects of these GABR variants on GABA(A) receptor biogenesis and channel function. We found that defects in receptor gating were the common deficiency of GABRA1 and GABRB2 Dravet syndrome variants, while mainly trafficking defects were found with the GABRG2 (c.269C>G, p. T90R) variant. It seems that variants in α1 and β2 subunits are less tolerated than in γ2 subunits, since variant α1 and β2 subunits express well but were functionally deficient. This suggests that all of these GABR variants are all targeting GABR genes that encode the assembled α1β2γ2 receptor, and regardless of which of the three subunits are mutated, variants in genes coding for α1, β2 and γ2 receptor subunits make them candidate causative genes in the pathogenesis of Dravet syndrome. Oxford University Press 2021-03-11 /pmc/articles/PMC8176149/ /pubmed/34095830 http://dx.doi.org/10.1093/braincomms/fcab033 Text en © The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Article
Hernandez, Ciria C
Tian, XiaoJuan
Hu, Ningning
Shen, Wangzhen
Catron, Mackenzie A
Yang, Ying
Chen, Jiaoyang
Jiang, Yuwu
Zhang, Yuehua
Macdonald, Robert L
Dravet syndrome-associated mutations in GABRA1, GABRB2 and GABRG2 define the genetic landscape of defects of GABA(A) receptors
title Dravet syndrome-associated mutations in GABRA1, GABRB2 and GABRG2 define the genetic landscape of defects of GABA(A) receptors
title_full Dravet syndrome-associated mutations in GABRA1, GABRB2 and GABRG2 define the genetic landscape of defects of GABA(A) receptors
title_fullStr Dravet syndrome-associated mutations in GABRA1, GABRB2 and GABRG2 define the genetic landscape of defects of GABA(A) receptors
title_full_unstemmed Dravet syndrome-associated mutations in GABRA1, GABRB2 and GABRG2 define the genetic landscape of defects of GABA(A) receptors
title_short Dravet syndrome-associated mutations in GABRA1, GABRB2 and GABRG2 define the genetic landscape of defects of GABA(A) receptors
title_sort dravet syndrome-associated mutations in gabra1, gabrb2 and gabrg2 define the genetic landscape of defects of gaba(a) receptors
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176149/
https://www.ncbi.nlm.nih.gov/pubmed/34095830
http://dx.doi.org/10.1093/braincomms/fcab033
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