Altered inhibitory synapses in de novo GABRA5 and GABRA1 mutations associated with early onset epileptic encephalopathies
| Autor: | Robert L. Macdonald, Dingding Shen, Ningning Hu, Hongmin Zhu, Yuwu Jiang, Wenshu XiangWei, Yujia Zhang, Zhaohui Sun, Lifang Dai, Changhong Ding, Ciria C. Hernandez, Wangzhen Shen, Jiasheng Hu, Andre H. Lagrange |
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| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Protein subunit Primary Cell Culture GABRA5 Mutant Biology medicine.disease_cause gamma-Aminobutyric acid Membrane Potentials Young Adult 03 medical and health sciences 0302 clinical medicine Intellectual Disability medicine Humans Genetic Predisposition to Disease Child Receptor gamma-Aminobutyric Acid Mutation Epilepsy GABAA receptor Miniature Postsynaptic Potentials Original Articles Receptors GABA-A Molecular biology 030104 developmental biology Child Preschool Synapses biology.protein Female Neurology (clinical) Receptor clustering 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Brain |
| ISSN: | 1460-2156 0006-8950 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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