机构：[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, 100034, China[4]Center of Epilepsy, Beijing Institute for Brain Disorders, Beijing 100069, 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 200025, 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 100045, China临床科室职能科室临床流行病与循证医学中心泌尿外科小儿神经科首都医科大学附属北京儿童医院[9]Epilepsy center of Yuquan Hospital, Tsinghua University, Beijing 100040, China[10]Department of Neurology, Wuhan Children’s Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430016, China
We performed next generation sequencing on 1696 patients with epilepsy and intellectual disability using a gene panel with 480 epilepsy-related genes including all GABA(A) 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 alpha 5(V294F and S413F) and alpha 1(P260S and L296S/W315L) subunit residue substitutions were all in transmembrane domains, while the alpha 1(R112Q and N115R) subunit residue substitutions were in the N-terminal GABA binding domain. Using multidisciplinary approaches, we compared effects of mutant GABA(A) receptor alpha 5 and alpha 1 subunits on the properties of recombinant alpha 5 beta 3 gamma 2 and alpha 1 beta 3 gamma 2 GABA(A) receptors in both neuronal and non-neuronal cells and characterized their effects on receptor clustering, biogenesis and channel function. GABA(A) receptors containing mutant alpha 5 and alpha 1 subunits all had reduced cell surface and total cell expression with altered endoplasmic reticulum processing, impaired synaptic clustering, reduced GABA(A) 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.
基金：
NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [RO1 NS 33300]
第一作者机构：[1]Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA[2]Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA[*1]Life Sciences Institute, University of Michigan, 210 Washtenaw Ave. Room 6115 Ann Arbor, MI 48109–2216, USA
共同第一作者：
通讯作者：
通讯机构：[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, 100034, China[4]Center of Epilepsy, Beijing Institute for Brain Disorders, Beijing 100069, China[*1]Life Sciences Institute, University of Michigan, 210 Washtenaw Ave. Room 6115 Ann Arbor, MI 48109–2216, USA[*2]Department of Neurology, Vanderbilt University Medical Center, 465 21st Ave. South. MRB III, Suite 6140 Nashville, TN - 37240–7915, USA[*3]Department of Pediatrics and Pediatric Epilepsy Center, Peking University First Hospital, No.1 Xi’an Men Street, West District, Beijing 100034, China
推荐引用方式(GB/T 7714)：
Hernandez Ciria C.,XiangWei Wenshu,Hu Ningning,et al.Altered inhibitory synapses in de novo GABRA5 and GABRA1 mutations associated with early onset epileptic encephalopathies[J].BRAIN.2019,142(7):1938-1954.doi:10.1093/brain/awz123.
APA：
Hernandez, Ciria C.,XiangWei, Wenshu,Hu, Ningning,Shen, Dingding,Shen, Wangzhen...&Macdonald, Robert L..(2019).Altered inhibitory synapses in de novo GABRA5 and GABRA1 mutations associated with early onset epileptic encephalopathies.BRAIN,142,(7)
MLA：
Hernandez, Ciria C.,et al."Altered inhibitory synapses in de novo GABRA5 and GABRA1 mutations associated with early onset epileptic encephalopathies".BRAIN 142..7(2019):1938-1954
医学