A de novo missense mutation of GABRB2 causes early myoclonic encephalopathy

Atsushi Ishii, Jing Qiong Kang, Cara C. Schornak, Ciria C. Hernandez, Wangzhen Shen, Joseph C. Watkins, Robert L. Macdonald, Shinichi Hirose

Research output: Research - peer-reviewArticle

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Abstract

Background 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. Methods 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. Results We discovered a de novo heterozygous missense mutation (c.859A>C [ p.Thr287Pro]) in the GABRB2-encoded β2 subunit of the GABAA receptor in an infant with EME. No GABRB2 mutations were found in three other EME cases or in 166 patients with infantile spasms. GABAA receptors bearing the mutant ß2 subunit were poorly trafficked to the cell membrane and prevented β2 subunits from trafficking to the cell surface. The peak amplitudes of currents from GABAA receptors containing only mutant ß2 subunits were smaller than that of those from receptors containing only wild-type ß2 subunits. The decrease in peak current amplitude (96.4% reduction) associated with the mutant GABAA receptor was greater than expected, based on the degree to which cell surface expression was reduced (66% reduction). Conclusion This mutation has complex functional effects on GABAA receptors, including reduction of cell surface expression and attenuation of channel function, which would significantly perturb GABAergic inhibition in the brain.

LanguageEnglish (US)
JournalJournal of Medical Genetics
Volume54
Issue number3
DOIs
StatePublished - Mar 1 2017

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Missense Mutation
GABA-A Receptors
Epileptic Encephalopathy, Early Infantile, 3
Mutation
Genes
Epilepsy
Infantile Spasms
Myoclonus
Ion Channels
gamma-Aminobutyric Acid
Electroencephalography
Seizures
Cell Membrane
Brain

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Ishii, A., Kang, J. Q., Schornak, C. C., Hernandez, C. C., Shen, W., Watkins, J. C., ... Hirose, S. (2017). A de novo missense mutation of GABRB2 causes early myoclonic encephalopathy. Journal of Medical Genetics, 54(3). DOI: 10.1136/jmedgenet-2016-104083

A de novo missense mutation of GABRB2 causes early myoclonic encephalopathy. / Ishii, Atsushi; Kang, Jing Qiong; Schornak, Cara C.; Hernandez, Ciria C.; Shen, Wangzhen; Watkins, Joseph C.; Macdonald, Robert L.; Hirose, Shinichi.

In: Journal of Medical Genetics, Vol. 54, No. 3, 01.03.2017.

Research output: Research - peer-reviewArticle

Ishii, A, Kang, JQ, Schornak, CC, Hernandez, CC, Shen, W, Watkins, JC, Macdonald, RL & Hirose, S 2017, 'A de novo missense mutation of GABRB2 causes early myoclonic encephalopathy' Journal of Medical Genetics, vol 54, no. 3. DOI: 10.1136/jmedgenet-2016-104083
Ishii A, Kang JQ, Schornak CC, Hernandez CC, Shen W, Watkins JC et al. A de novo missense mutation of GABRB2 causes early myoclonic encephalopathy. Journal of Medical Genetics. 2017 Mar 1;54(3). Available from, DOI: 10.1136/jmedgenet-2016-104083
Ishii, Atsushi ; Kang, Jing Qiong ; Schornak, Cara C. ; Hernandez, Ciria C. ; Shen, Wangzhen ; Watkins, Joseph C. ; Macdonald, Robert L. ; Hirose, Shinichi. / A de novo missense mutation of GABRB2 causes early myoclonic encephalopathy. In: Journal of Medical Genetics. 2017 ; Vol. 54, No. 3.
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N2 - Background 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. Methods 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. Results We discovered a de novo heterozygous missense mutation (c.859A>C [ p.Thr287Pro]) in the GABRB2-encoded β2 subunit of the GABAA receptor in an infant with EME. No GABRB2 mutations were found in three other EME cases or in 166 patients with infantile spasms. GABAA receptors bearing the mutant ß2 subunit were poorly trafficked to the cell membrane and prevented β2 subunits from trafficking to the cell surface. The peak amplitudes of currents from GABAA receptors containing only mutant ß2 subunits were smaller than that of those from receptors containing only wild-type ß2 subunits. The decrease in peak current amplitude (96.4% reduction) associated with the mutant GABAA receptor was greater than expected, based on the degree to which cell surface expression was reduced (66% reduction). Conclusion This mutation has complex functional effects on GABAA receptors, including reduction of cell surface expression and attenuation of channel function, which would significantly perturb GABAergic inhibition in the brain.

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