2. Academic Validation
  3. Altered inhibitory synapses in de novo GABRA5 and GABRA1 mutations associated with early onset epileptic encephalopathies

Altered inhibitory synapses in de novo GABRA5 and GABRA1 mutations associated with early onset epileptic encephalopathies

  • Brain. 2019 Jul 1;142(7):1938-1954. doi: 10.1093/brain/awz123.
Ciria C Hernandez 1 2,  Wenshu XiangWei 3 4,  Ningning Hu 1,  Dingding Shen 5 6,  Wangzhen Shen 1,  Andre H Lagrange 1 7,  Yujia Zhang 8,  Lifang Dai 8,  Changhong Ding 8,  Zhaohui Sun 9,  Jiasheng Hu 10,  Hongmin Zhu 10,  Yuwu Jiang 3 4,  Robert L Macdonald 1
Affiliations

Affiliations

  • 1 Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 2 Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA.
  • 3 Department of Pediatrics and Pediatric Epilepsy Center, Peking University First Hospital, Beijing, China.
  • 4 Center of Epilepsy, Beijing Institute for Brain Disorders, Beijing, China.
  • 5 The Graduate Program of Neuroscience, Vanderbilt University, Nashville, TN, USA.
  • 6 Department of Neurology, Rui Jin Hospital, Shanghai Jiao Tong University, School of Medicine. Shanghai, China.
  • 7 Department of Pharmacology and Molecular Physiology and Biophysics, Vanderbilt University, and the Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN, USA.
  • 8 Department of Neurology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China.
  • 9 Epilepsy center of Yuquan Hospital, Tsinghua University, Beijing, China.
  • 10 Department of Neurology, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
PMID: 31056671 DOI: 10.1093/brain/awz123
Abstract

We performed next generation Sequencing on 1696 patients with epilepsy and intellectual disability using a gene panel with 480 epilepsy-related genes including all GABAA receptor subunit genes (GABRs), and we identified six de novo GABR mutations, two novel GABRA5 mutations (c.880G>T, p.V294F and c.1238C>T, p.S413F), two novel GABRA1 mutations (c.778C>T, p.P260S and c.887T>C, p.L296S/c.944G>T, p.W315L) and two known GABRA1 mutations (c.335G>A, p.R112Q and c.343A>G, p.N115D) in six patients with intractable early onset epileptic encephalopathy. The α5(V294F and S413F) and α1(P260S and L296S/W315L) subunit residue substitutions were all in transmembrane domains, while the α1(R112Q and N115R) subunit residue substitutions were in the N-terminal GABA binding domain. Using multidisciplinary approaches, we compared effects of mutant GABAA receptor α5 and α1 subunits on the properties of recombinant α5β3γ2 and α1β3γ2 GABAA receptors in both neuronal and non-neuronal cells and characterized their effects on receptor clustering, biogenesis and channel function. GABAA receptors containing mutant α5 and α1 subunits all had reduced cell surface and total cell expression with altered endoplasmic reticulum processing, impaired synaptic clustering, reduced GABAA receptor function and decreased GABA binding potency. Our study identified GABRA5 as a causative gene for early onset epileptic encephalopathy and expands the mutant GABRA1 phenotypic spectrum, supporting growing evidence that defects in GABAergic neurotransmission contribute to early onset epileptic encephalopathy phenotypes.

Keywords

GABRA1; GABRA5; GABAA receptors; GABAergic synapses; encephalopathy.

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