Dravet syndrome-associated mutations in GABRA1, GABRB2 and GABRG2 define the genetic landscape of defects of GABAA receptors

Ciria C Hernandez; XiaoJuan Tian; Ningning Hu; Wangzhen Shen; Mackenzie A Catron; Ying Yang; Jiaoyang Chen; Yuwu Jiang; Yuehua Zhang; Robert L Macdonald

doi:10.1093/braincomms/fcab033

Dravet syndrome-associated mutations in GABRA1, GABRB2 and GABRG2 define the genetic landscape of defects of GABA_A receptors

Brain Commun. 2021 Mar 11;3(2):fcab033. doi: 10.1093/braincomms/fcab033. eCollection 2021.

Authors

Ciria C Hernandez^{1

2}, XiaoJuan Tian^{3

4}, Ningning Hu², Wangzhen Shen², Mackenzie A Catron^{2

5}, Ying Yang³, Jiaoyang Chen³, Yuwu Jiang^{3

6}, Yuehua Zhang³, Robert L Macdonald²

Affiliations

¹ Life Sciences Institute, University of Michigan, Ann Arbor, MI 48198, USA.
² Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37240, USA.
³ Department of Pediatrics and Pediatric Epilepsy Center, Peking University First Hospital, Beijing 100034, China.
⁴ Department of Neurology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China.
⁵ Neuroscience Graduate Program, Vanderbilt University, Nashville, TN 37240, USA.
⁶ Center of Epilepsy, Beijing Institute for Brain Disorders, Beijing 100069, China.

Abstract

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.

Keywords: Dravet syndrome-associated mutations; GABRA1; GABRB2; GABRG2; PIP2.

Grants and funding

R01 NS033300/NS/NINDS NIH HHS/United States