title: Ade novomissense mutation ofGABRB2causes early myoclonic encephalopathy.
abstract: Early myoclonic encephalopathy (EME), a disease with a devastating prognosis, is characterised by neonatal onset of seizures and massive myoclonus accompanied by a continuous suppression-burst EEG pattern. Three genes are associated with EMEs that have metabolic features. Here, we report a pathogenic mutation of an ion channel as a cause of EME for the first time.
  
  
  
  Sequencing was performed for 214 patients with epileptic seizures using a gene panel with 109 genes that are known or suspected to cause epileptic seizures. Functional assessments were demonstrated by using electrophysiological experiments and immunostaining for mutant γ-aminobutyric acid-A (GABAA) receptor subunits in HEK293T cells.
  
  
  
  We discovered ade novoheterozygous missense mutation (c.859A>C [p.Thr287Pro]) in theGABRB2-encoded β2 subunit of the GABAAreceptor in an infant with EME. NoGABRB2mutations were found in three other EME cases or in 166 patients with infantile spasms. GABAAreceptors bearing the mutant β2 subunit were poorly trafficked to the cell membrane and prevented γ2 subunits from trafficking to the cell surface. The peak amplitudes of currents from GABAAreceptors containing only mutant β2 subunits were smaller than that of those from receptors containing only wild-type β2 subunits. The decrease in peak current amplitude (96.4% reduction) associated with the mutant GABAAreceptor was greater than expected, based on the degree to which cell surface expression was reduced (66% reduction).
  
  
  
  This mutation has complex functional effects on GABAAreceptors, including reduction of cell surface expression and attenuation of channel function, which would significantly perturb GABAergic inhibition in the brain.
authors: Department of Pediatrics, School of Medicine, Fukuoka University, Fukuoka, Japan.
authors: Atsushi
authors: A
authors: Ishii
authors: Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors: Jing-Qiong
authors: JQ
authors: Kang
authors: Neuroscience Graduate Program, Vanderbilt University, Nashville, Tennessee, USA.
authors: Cara C
authors: CC
authors: Schornak
authors: Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors: Ciria C
authors: CC
authors: Hernandez
authors: Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors: Wangzhen
authors: W
authors: Shen
authors: Department of Mathematics, University of Arizona, Tucson, Arizona, USA.
authors: Joseph C
authors: JC
authors: Watkins
authors: Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors: Robert L
authors: RL
authors: Macdonald
authors: Department of Pediatrics, School of Medicine, Fukuoka University, Fukuoka, Japan.
authors: Shinichi
authors: S
authors: Hirose
mesh_terms: D001921:Brain / Q000000981:diagnostic imaging / Q000503:physiopathology; D018360:Crystallography, X-Ray; D004569:Electroencephalography; D057809:HEK293 Cells; D006801:Humans; D007223:Infant; D008297:Male; D008958:Models, Molecular; D020125:Mutation, Missense; D053578:Opsoclonus-Myoclonus Syndrome / Q000235:genetics* / Q000503:physiopathology; D011963:Receptors, GABA-A / Q000737:chemistry / Q000235:genetics*; D012640:Seizures / Q000235:genetics* / Q000503:physiopathology; D013036:Spasms, Infantile / Q000235:genetics* / Q000503:physiopathology
chemical_list: C495710:GABRB2 protein, human; D011963:Receptors, GABA-A
keywords: Cl<sup>-</sup> current; Epilepsy and seizures; GABA<sub>A</sub> receptor; epileptic encephalopathy; trafficking